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RC660  .J784  1915    Carbohydrate  utiliza 

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CARBOHYDRATE   UTILIZATION 
IN    DIABETES 

Based  on  Studies  of  the  Respiration,  Urine  and  Blood 


ELLIOTT     P.     JOS  LIN,     M.  D. 

BOSTON 


Reprinted    from    the    Archives    nf    Internal    Medicine 
November,  1915,  Vol.  xvi,  />/>.  693.-732 


CHICACO 

American   Medical  Association 

Five  Hundred  and  Thirty-Five  North   Dearborn   Street 

1915 


RCUo 
1315 


CARBOHYDRATE     UTILIZATION     IN     DIABETES 

BASED    ON    STUDIES    OF    THE    RESPIRATION,    URINE    AND    BLOOD  * 

ELLIOTT    p.    JOSLIN,    M.D. 

BOSTON 

In  the  classical  work  of  Naunyn^  on  diabetes  mellitus  occurs  the 
following  passage :  "In  general,  even  in  severe  diabetes,  at  least  in 
man,  the  carbohydrates  ingested  are  not  completely  excreted  in  the 
urine  again  as  sugar.  A  portion  of  the  starch,  as  well  as  of  the  dex- 
trose, will  be  burned  in  the  organism."  This  view  was  also  shared  by 
Kulz.  Naunyn,  however,  refers  to  a  case  in  which  von  Mering  records 
an  excretion  of  all  the  sugar  ingested,  and  attention  is  called  in  the 
report  of  the  cases  of  Kulz  to  four  instances  in  which  apparently  a 
similar  condition  existed. 

Von  Noorden^  defines  diabetes  as  "a  disease  in  which  the  capability 
of  the  organism  adequately  to  burn  grape  sugar  is  pathologically 
lowered,"  and  in  another  place^  he  says :  "One  cannot  help  thinking 
that,  in  man,  even  when  death  has  resulted  from  coma,  the  diabetes 
has  not  always  been  'quite  complete' — that  is  to  say,  the  pathological 
processes  which  produce  diabetes  have  not  developed  so  far,  and  the 
factors  which  favor  the  storing  up  of  glycogen  have  not  been  so  com- 
pletely destroyed  as  is  the  case  in  a  dog  whose  pancreas  has  been 
entirely  ablated." 

Notwithstanding  all  the  work  on  diabetes,  this  question  of  the  utili- 
zation of  carbohydrates  in  human  diabetes  has  not  been  settled.  In 
diabetic  dogs  evidence  has  accumulated  pointing  to  the  complete  loss 
of  this  power  to  utilize  carbohydrate,  and  the  work  of   Alurlin  and 


*  From  the  Nutrition  Laboratory  of  the  Carnegie  Institution  of  Washington, 
Boston. 

*  I  wish  to  acknowledge  my  grateful  appreciation  of  the  help  received  from 
Mr.  Emmes,  Miss  Babcock,  Miss  Tompkins,  Miss  Corson  and  Miss  Sandiford 
of  the  Nutrition  Laboratory,  as  also  my  indebtedness  to  Mr.  Higgins,  who  con- 
trolled several  of  the  experiments  with  the  Tissot  apparatus,  and  to  my  secre- 
tary, Miss  Helen  Leonard,  for  cheerful  work  on  long  computations  and  puzzling 
charts. 

L  Naunyn:  Der  Diabetes  Melitus,  1906,  p.  173. 

2.  Von  Noorden :    Zuckerkrankheit,  Ed.  6,  1912.  p.  2. 

3.  Von   Noorden :    Metabolism   and   Practical   Medicine,   1907,  iii,  542. 


Cramer*  has  given  definite  results  on  this  point,  although  so  recent  a 
writer  as  Landsberg,^  working  from  a  different  point  of  view  with 
other  animals,  comes  to  the  opposite  conclusion.  The  present  paper  is 
concerned  with  diabetes  in  man  and  I  wish  to  call  attention  to  certain 
observations  bearing  on  this  problem  which  are  related  to  the  body 
weight,  the  urine,  the  storage  of  carbohydrate  in  the  body,  the  respira- 
tory metabolism  of  diabetics  both  fasting  and  following  the  administra- 
tion of  food  and  the  remarkable  disappearance  of  acidosis  in  diabetics 
with  prolonged  fasting,  which  is  associated  with  a  rise  in  their  respira- 
tory quotient. 

I.    THE    INFLUENCE    OF    WEIGHT    ON    THE    DETERMINATION    OF    THE 
UTILIZATION    OF    CARBOHYDRATES    IN    DIABETES 

The  changes  in  weight  which  occur  in  a  normal  individual,  fol- 
lowing a  slight  increase  of  the  carbohydrate  in  the  diet,  are  so  striking 
that  one  might  hastily  conclude  that  a  study  of  the  weights  of  a 
diabetic  patient  would  give  some  idea  as  to  his  utilization  of  starch 
and  sugar.  A  closer  scrutiny  of  the  problem,  however,  reveals  many 
difficulties.  In  the  first  place,  the  diet  employed  in  most  cases  of  dia- 
betes and  all  severe  cases,  is  low  in  carbohydrates,  and  seldom  reaches 
10  per  cent,  of  that  of  normal  individuals.  In  other  words,  it  amounts 
to  less  than  50  gm.  carbohydrate — 200  calories — per  day.  The  effect 
of  200  calories  on  the  weight  is  possible  of  determination  theoretically, 
but  practically  such  an  experiment  is  difficult  because  the  protein,  fat 
and  carbohydrate  must  be  kept  at  uniform  levels  for  a  long  period. 
But  in  a  severe  case  of  diabetes  some  of  even  this  small  amount  is  lost 
in  the  urine,  which  renders  the  available  carbohydrate  for  increasing 
the  weight  still  less.  There  are  other  complications.  In  a  severe  case 
of  diabetes,  the  patient  with  50  gm.  of  carbohydrate  in  the  diet,  usually 
excretes  more  than  50  gm.  of  sugar  in  the  urine,  and  it  is  difficult  to 
assign  in  proper  proportion  this  excess  of  urinary  sugar  between  the 
carbohydrate  ingested  and  the  carbohydrate  already  stored  in  the  body 
on  the  one  hand,  and  the  protein  simultaneou.sly  ingested  and  the  body 
protein  on  the  other. 

Remarkable  changes  in  the  weight  of  normal  as  well  as  of  diabetic 
patients  will  also  occur,  although  the  caloric  value  of  the  diet  remains 
constant,  if  the  proportion  of  fat  to  carbohydrate  is  altered.  A  diet 
rich  in  carbohydrate  brings  about  an  increase  in  weight,  whereas  a  diet 
of  exactly  the  same  number  of  calories,  although  chiefly  made  up  of 
fat,  lowers  the  weight.     These  changes  undoubtedly  are  due  simply 


4.  Murlin  and  Cramer :    Jour.  Biol.  Chem.,  1913,  xv,  365. 

5.  Landsberg:    Deutsch.  Arch.  f.  klin.  Med.,  1914,  cxv,  465. 


to  the  retention  of  water  by  the  tissues  on  a  carbohydrate  diet,  and 
loss  of  water  on  a  fat  diet.  Such  changes  appear  reasonable  because 
the  storage  of  1  gni.  of  carbohydrate  in  the  body  demands  the  retention 
of  3  gm.  of  water,  1  gm.  of  protein  requires  the  storage  of  0.75  gm. 
of  water,  and  1  gm.  of  fat  requires  only  0.1  gm.  of  water.  These 
changes  are  well  illustrated"  by  Table  1. 


TABLE   1. 


-Changes   in    Weight   Under   Fat   and   Carbohydrate   Diets 

Carbohydrate  Diet 


Food   and    Drink 

Body  Weight 
kilos 

Gain    (-f) 

Date 

Solid  Matter 
gm. 

Water 
gm. 

Total 
gm. 

or  Loss  ( — ) 
gm. 

4/lfi/04 
4/16-17/04 
4/17-18/04 
4/18-19/04 

970 
966 
966 

3.577 
3.5S3 
3,491 

V.547 
4.519 

4,457 

75.086 
75.443 
75.414 
75.269 

+"357 

—  29 

—  143 

Fat  Diet 


4/19-20/04 
4/20-21/04 
4/21-22/04 


750 

745 
747 


3,108 
4.150 
4,152 


3,859 
4,896 
4,899 


74.319 
73.480 
72.5.28 


—  950 

—  839 

—  952 


Average  gain   per  day,  carbohydrate  diet,   +   61   gm. 
Average  loss  per  day,  fat  diet,  — 914  gm. 
Water  stored  per  day,  carbohydrate  period,  +  165  gm. 
Water  lost  per  day,  fat  period,  —  906  gm. 

It  is  important  for  the  clinician  to  bear  this  in  mind,  because  it 
explains  the  rapid  change  in  weight  which  often  follows  the  initial 
diminution  of  the  carbohydrate  in  the  diet  of  diabetic  patients  and  its 
replacement  with  fat. 

An  increase  in  weight  following  a  marked  increase  of  carbohydrate 
in  the  diet  is  strikingly  illustrated  in  severe  diabetic  patients  under  the 
oatmeal  treatment.'^  Under  these  conditions  the  weight  may  rise  4.5 
kg.  in  one  or  twp  days.  Undoubtedly  you  all  have  seen  edema  during 
the  course  of  an  oatmeal  cure.  It  is  significant  that  some  of  these 
cases  show  little  or  no  carbohydrate  in  the  urine.  I  cannot  give  proof 
that  patients  showing  this  increase  in  weight  fail  to  give  evidence  of 
burning  more  than  a  trifling  amount  of  carbohydrate,  but  from  other 
similar  cases  I  suspect  this  often  to  be  the  case.  This  point  deserves 
further  study.  I  think,  however,  that  there  will  be  general  agreement 
that  the  gain  in  weight  following  the  sudden  introduction  of  large 
quantities  of  carbohydrate  is  accounted  for  by  the  storage — tempo- 
rarily, perhaps — of  carbohydrate  in  the  body.  That  this  storage  or 
delay  of  excretion  is  accentuated  in  the  presence  of  diseased  kidneys 


6.  Benedict  and  Joslin :    A  Study  of  Metabolisin  in  Severe  Diabetes,  Carnegie 
Institute  of  Washington,  1912,  Pub.  No.  176,  p.  93. 

7.  Mirowsky:    Deutsch.  med.  Wchnschr.,  1912,  xxxviii,  459. 


is  common  knowledge.    Barrenscheen^  showed  that  milk  sugar  excre- 
tion was  delayed  on  the  day  following  an  oatmeal  cure. 

.The  administration  of  sodium  bicarbonate  is  frequently  followed 
by  a  gain  in  weight.  Thus,^  in  Case  220,  the  changes  in  weight  during 
the  administration  of  sodium  bicarbonate  were  as  shown  in  Table  2. 


TABLE  2. — Changes   in   Weight   During  the   Administration   of   Sodium 

Bicarbonate 


Date 

Sodium 

Bicarbonate 

gm. 

Body  Weight 
kilos. 

Date 

Sodium 

Bicarbonate 

gm. 

Body  Weight 
kilos. 

11/2 
11/3 
11/4 
11/S 
11/6 

0 
0 
0 
0 
20 

48.1 
48.6 
49.0 
48.6 
49.3 

11/  7 
11/  8 
11/  9 
11/10 
11/11 

20 
20 
20 
20 
20 

S0.7 
51.5 
52.4 
53.3 
53.3 

In  order  to  show  that  this  gain  in  weight  was  not  directly  due  to 
the  alkali,  but  rather  to  retention  of  salt,  the  weights  of  another  dia- 
betic patient.  Case  135,  were  taken  while  on  a  salt-free  diet^°  (Table  3). 

TABLE    3. — Changes    in    Weight    on    a    Salt-Free    Diet 


Intake 

Urine 

Date, 
1908 

NaHCOs 
Gm. 

Carb., 
Gm. 

Pro- 
tein, 
Gm. 

Fat, 
Gm. 

Alco- 
hol, 
Gm. 

Liquids 
c.c. 

Vol., 
c.c. 

N, 
Gm. 

NHs, 
Gm. 

Acetone 

and 

Diacetic 

Acid.,Gm. 

Beta- 
oxy. 

Acid, 
Gm. 

P2O5, 
Gm. 

01., 
Gm. 

Sugar, 
Gm. 

W 
LI 

L/26 

0 

135 

110 

185 

3,500 

3,720 

21.8 

4.2 

7.9 

29 

4.4 

8.2 

160 

8€ 

L/27 

0 

135 

UO 

185 

3,500 

3,940 

19. 0' 

4.3 

7.8 

29 

4.5 

6.3 

165 

8S 

L/28 

0 

135 

110 

185 

3,500 

3,210 

20.5 

4.4 

7.3 

24 

4.6 

5.9 

160 

86 

L/29 

0 

135 

90 

155 

3,500 

3,210 

19.2 

4.1 

7.3 

26 

4.2 

4.8 

163 

8S 

L/30 

25 

135 

70 

185 

3,500 

3,190 

16.3 

3.5 

8.7 

33 

4.1 

1.6 

146 

85 

L/31 

25 

120 

60 

95 

23 

5,370 

4,600 

19.1 

4-.3 

12.6 

51 

5.1 

2.3 

146 

8S 

!/l 

37 

130 

100 

130 

45 

5,250 

4,050 

18.7 

3.3 

10.7 

39 

4.3 

2.0 

137 

82 

!/2 

52 

70 

60 

95 

45 

5,370 

3,510 

16.0 

3.5 

10.2 

37 

3.9 

2.1 

121 

81 

!/3 

•• 

15 

15 

30 

45 

800 

260 

15.0 

... 

86 

It  will  be  seen  that  while  on  the  salt-free  diet  the  weight  steadily 
fell,  and  despite  the  administration  of  sodium  bicarbonate  later,  no 
increase  in  weight  occurred.  This  observation  has  been  elsewhere  con- 
firmed. I  might  here  make  the  clinical  observation  that  a  salt-free 
diet  in  diabetes  is  inadvisable.    It  is  also  interesting  that  I  have  never 


8.  Barrenscheen :    Biochem.  Ztschr.,  1912,  xxxix,  232. 

9.  Benedict  and  Joslin :    Loc.  cit.   (Note  6)  p.  94. 

10.  Joslin  and  Goodall:    Jour.  Am.  Med.  Assn.,  1908,  li,  727. 


seen  the  death  from  diabetic  coma  of  a  diabetic  patient  who  had  dropsy, 
nor  have  I  encountered  such  in  the  literature. 

The  simple  enumeration  of  these  various  facts  affecting  the  weight 
shows  how  complicated  is  the  determination  of  the  utilization  of  car- 
bohydrate from  it  alone.  Changes  in  weight,  however,  do  afford,  when 
combined  with  other  methods  of  clinical  investigation,  new  fields  for 
work. 

The  changes  in  weight  which  a  healthy  fasting  man  undergoes  at 
the  beginning  of  a  fast  are  known.  The  fasting  man  at  the  Nutrition 
Laboratory  lost  2,850  gm.  in  three  days,  and  consumed  during  these 
three  days  body  substance  equivalent  to  161  gm.  of  protein,  149  gm. 
of  carbohydrate  and  407  gm.  of  fat.  It  is  possible  that  from  a  series 
of  observations  on  diabetic  patients  similarly  fasted,  conclusions  of 
value  as  to  the  storage  of  carbohydrate  in  the  body  might  be  secured. 
Ten  of  m)'-  patients  who  were  available  for  this  purpose  showed  on 
an  initial  fast  a  loss  of  weight  considerably  less,  and  occasionally  a 
gain  in  weight  was  recorded.  Following  the  termination  of  the  fast, 
although  very  little  food  was  given,  an  increase  in  weight  out  of 
proportion  to  the  amount  of  food  given  was  almost  invariably 
observed. 

In  one  case  no  mineral  waters  or  alkalies  were  taken,  and  yet  gain 
in  weight  occurred  during  fasting.  It  is  not  unexpected  that  the  gain 
in  weight  was  often  coincident  with  a  fall  in  the  excretion  of  urine. 
A  gain  in  weight  during  fasting  raises  the  question  as  to  whether  new 
carbohydrate  has  not  been  formed  in  the  body,  and  as  a  result  of  its 
formation  water  retained.  This  line  of  investigation  deserves  atten- 
tion. It  will  be  referred  to  later  in  the  discussion  of  severe  cases  of 
diabetes  treated  by  prolonged  fasting,  the  method  which  Dr.  F.  M. 
Allen"  has  had  the  courage  to  introduce  and  has  so  accurately  defined 
that  it  is  safe  for  any  practitioner  to  employ. 

II.  THE  UTILIZATION  OF  CARBOHYDRATES  BASED  ON  INTAKE  IN  DIET 
AND  OUTGO  IN   URINE 

The  comparison  between  the  carbohydrate  ingested  and  the  sugar 
excreted  in  the  urine  is  the  common  method  of  determining  the  utiliza- 
tion of  carbohydrates.  It  would  appear  to  be  a  simple  procedure,  but, 
as  a  matter  of  fact,  the  problem  is  far  more  difificult  than  has  heretofore 
been  considered.  Your  attention  is  first  directed  to  the  possibilities  of 
error  in  reckoning  the  carbohydrate  in  the  diet.  Most  severe  diabetics 
under  careful  observation  live  on  diets  low  in  carbohydrate,  seldom  in 
excess  of  50  em.     Therefore  errors  of  5  gm.  in  the  estimation  of 


11.  Allen:    Jour.   Am.  Med.   Assn.,   1914,  Ixiii,  939;   Boston   Med.  and   Surg. 
Jour.,  1915,  clxxv,  241. 


carbohydrates,  though  actually  small,  are  proportionately  large.  It  is 
seldom  that  the  actual  quantity  of  carbohydrate  in  the  diet  has  been 
analyzed.  In  many  of  the  cases  food  has  not  even  been  carefully 
weighed,  and  approximate  portions  of  food  have  been  supposed  to 
contain  definite  quantities  of  carbohydrate.  Take,  for  ex^taple, 
cream:  The  quantity  of  carbohydrate  contained  in  half  a  pint  may 
vary  5  gm.,  making  an  error  of  10  per  cent.,  if  the  total  carbohydrate 
for  the  day  amounted  to  50  gm.,  or  20  per  cent,  if  limited  to  25  grams. 

Vegetables  constitute  a  considerable  proportion  of  the  diet  of  these 
patients  with  severe  diabetes.  Often  in  the  literature — and  I  plead 
guilty  to  the  charge — the  quantity  of  carbohydrate  in  the  mixture  of 
vegetables  chosen  from  those  containing  less  than  10  per  cent,  carbo- 
h3'drate  for  the  day,  has  been  roughly  estimated.  Recently  I  have 
taken  more  careful  account  of  the  amount  of  vegatables  eaten,  and 
it  has  come  out  that  the  quantity  of  vegetables  prescribed  and  eaten 
frequently  varies  from  300  gm.  to  1,000  gm.  Any  accurate  computa- 
tion, therefore,  of  a  carbohydrate  balance  must  be  based  not  alone  on 
the  total  quantity  of  vegetables  eaten  in  the  day,  but  on  the  actual 
quantity  of  each  vegetable,  even  in  these  low  carbohydrate  groups. 
Furthermore,  varieties  of  the  same  vegetable  vary  in  percentage  of 
carbohydrate.  It  makes  a  difference  of  5  gm.  in  a  day  whether  500  gm. 
vegetables  contain  1  per  cent,  more  or  less  of  carbohydrate.  But  this 
is  not  all.  Analyses  of  carbohydrate  in  vegetables  include  the  cellulose 
contained  in  them  as  well  as  the  starch  and  sugar.  How  much  shall 
we  subtract  from  our  total  carbohydrate  intake  on  account  of  this 
undigested  cellulose  which  is  lost  in  the  feces? 

The  other  foods  commonly  used  in  the  study  of  the  metabolism  of 
diabetic  patients  are  potato,  oatmeal,  bread,  fruit.  The  potato,  oat- 
meal and  bread  are  usually  carefully  weighed,  and  the  analyses  of 
these  foods  are  fairly  constant,  but  the  percentage  of  carbohydrate 
is  so  large  that  I  should  not  dare  to  be  positive  about  the  quantity  of 
carbohydrate  which  my  patient  received  unless  standard  varieties  of 
these  foods  were  employed.  With  fruit  frequent  errors  exist,  because 
usually  an  orange  or  grapefruit  is  allowed  and  seldom  the  actual 
weights  of  the  portions  eaten  are  determined.  A  further  error  occurs 
in  that  the  intake  of  carbohydrate  is  reckoned  indifferently  as  starch 
or  sugar.  As  a  matter  of  fact,  100  gm.  of  starch  when  converted  to 
sugar  amount  to  105  gm.  Errors  of  5  and  10  gm.  a  day  in  computing 
the  carbohydrate  intake  may  easily  occur  and  in  a  period  of  a  week 
form  notable  amounts,  from  35  to  70  gm.  Physiologists  and  physicians 
must  not  take  too  seriously  clinical  statements  about  the  carbohydrate 
in  the  diet,  and  greater  accuracy  must  be  employed  in  the  future. 
We  need,  first,  a  standard  test  diabetic  diet,  and,  second,  we  need  to 


employ  it  for  at  least  five  days.  Unfortunately,  even  at  the  end  of 
this  time  the  results  may  be  unsatisfactory,  because  the  condition  of 
the  patient's  tolerance  may  have  changed  in  this  period  either  for 
better  or  worse. 

The  estimation  of  sugar  in  the  urine  is  far  more  accurate  than  that 
of  the  carbohydrate  in  the  diet,  provided  the  analysis  is  made  in  one 
of  our  best  laboratories,  but  I  would  hesitate  to  accept  as  final  in 
accurate  computations  many  routine  analyses  made  in  private  practice 
or  in  hospitals.  Too  often  the  method  employed  in  the  estimation  of 
the  sugar  is  not  mentioned,  and  I  suspect  many  results  are  obtained 
with  the  polariscope  which  may  involve  an  error  of  20  gm.  or  more, 
owing  to  the  presence  of  levorotary  bodies.  Urinary  analyses,  how- 
ever, are  usually  far  and  away  ahead  in  accuracy  of  that  observed  in 
the  collection  and  measurement  of  the  urines  of  diabetic  patients.  The 
admirable  methods  adopted  in  the  ward  of  the  Russell  Sage  Institute  at 
Bellevue  Hospital  and  at  the  Rockefeller  Hospital  have  been  seldom 
followed  by  experimenters  in  the  past.  I  pass  over  errors  of  forgetful- 
ness  or  design  on  the  part  of  the  patients,  as  regards  both  diet  and 
collection  of  urine.  Dogs  may  not  be  any  more  honest,  but  we  do  not 
expose  them  to  temptation  or  trust  their  memory.  How  often  a 
patient  states  that  a  trifling  amount  of  urine  has  been  lost  at  stool! 
I  realize  this  is  trite,  but  a  good  share  of  the  arguments  based  on  the 
utilization  of  carbohydrate  rests  on  data  which  are  not  above  reproach. 

The  variability  of  excretion  of  urine  and  urinary  constituents  from 
day  to  day  is  another  source  of  error.  If  the  diet  is  not  constant  the 
variation  may  be  great.  In  one  of  our  tests  designed  to  determine  the 
utilization  of  levulose,  during  seven  days  prior  to  the  administration 
of  levulose  the  average  volume  of  urine  was  1,079  c.c.  On  the  day 
the  levulose  was  given  the  volume  of  urine  was  966  c.c,  the  next  day 
390  c.c,  and  on  the  following  day  it  amounted  to  1,175  c.c;  it  then 
returned  to  near  the  average  quantity.  Yet  the  habits  of  this  patient's 
daily  life  were  nearly  constant,  and  except  for  the  one  levulose  day 
changes  in  the  diet  were  not  extreme.  Such  marked  variations  in  the 
volume  of  the  urine  on  successive  days  must  be  reckoned  with,  because 
with  such  great  changes  in  volumes  of  urine,  the  quantities  of  the 
constituents  of  the  urine  change  too,  though  to  a  much  less  extent. 
In  this  same  case,  the  average  daily  excretion  of  nitrogen  for  the 
fifty-five  days  which  included  this  period  was  7 .Z  gm.,  but  on  the  day 
when  81  gm.  levulose  were  given  with  very  little  other  food,  it  fell  to 
6.53  gm.  and  on  the  next  day  to  4.34  gm.  This  low  point  was  never 
reached  by  this  same  patient  on  a  fasting  day,  and  the  quantity  of 
levulose  is  considerably  less  than  would  be  supposed  to  exert  so  strong 
a  positive  action,  particularly  when  delayed  or  diminished  oxidation 


8 

is  taken  into  consideration.  Consult  Table  4  and  also  chart  of  varia- 
tions in  excretion  of  urine  and  sugar  of  a  severe  diabetic  on  a  constant 
diet,  shown  further  on. 

TABLE  4. — Effect   of  Levulose 
Case  785.    Male,  aged  17.    Weight,  42  Kilos. 


Output 


Intake 


Vol., 
cc 

Diae. 
Acid 

Sugar, 
Gm. 

Nitrogen, 
,      Gm. 

Ammo- 
nia, Gm. 

Garb., 
Gm. 

Prot., 
Gm. 

Pat, 
Gm. 

Alcohol, 
Gm. 

Calo- 
ries 

1,079* 

+ 

ll.lt 

7.83 

.... 

17 

58 

127 

9 

1,506 

966 

+ 

7 

6.53 

0.69 

90t 

21 

30± 

3 

735 

390 

++ 

5 

4.34 

0.35 

20 

63 

110 

9 

1,385 

1,175 

+ 

3 

8.35 

0.74 

20± 

63 

110± 

9 

1,385± 

*  Average  for  previous  seven  days. 

t  None  on  six  days. 

X  Levulose,  81  gm.  Garb,  in  Diet  9 


gm.  in  the  form  of  vegetables. 


Experiments  designed  to  test  the  utilization  of  carbohydrate  should 
be  conducted  on  patients  who  are  in  equilibrium  both  as  regards 
weight  and  urinary  excretion. 


III.    THE    IMPORTANCE    AS    V/ELL    AS    THE    INFLUENCE    OF    CARBO- 
HYDRATE  STORED   IN   THE   BODY   ON   TFIE   UTIILIZATION    OF 
CARBOHYDRATE     INGESTED 

It  is  well  known  that  following  a  period  of  fasting  large  quantities 
of  carbohydrate  can  be  administered  without  subsequently  appearing 
in  the  urine.  The  best  illustration  of  this  is  von  Noorden's  oatmeal 
treatment.  Thus  Case  R.  of  the  Benedict  and  Joslin  series^^  showed 
a  positive  carbohydrate  balance  of  520  gm.  during  an  oatmeal  cure, 
although  he  never  after  this  cure  became  sugar-free  save  for  occasional 
days,  despite  rigorous  dieting.  A  more  spectacular  demonstration  is  the 
severe  diabetic  of  Klemperer,^^  who  took  100  gm.  of  glucose  in 
divided  portions  during  twenty-four  hours  without  more  than  a  few 
grams  appearing  in  the  urine.  Almost  as  striking  is  that  of  a  boy  of 
17  (Case  785)  who  came  to  me  in  the  twentieth  month  of  the  disease. 
By  consulting  Table  4  it  will  be  seen  that  only  7  gm.  of  sugar  appeared 
in  the  urine  following  an  intake  at  one  time  of  81  gm.  levulose, 
although  by  observations  before  and  after  the  tolerance  was  known  to 
be  low.    A  summary  of  his  metabolism  is  given  in  Table  5. 


12.  Benedict  and  Joslin:    Loc.  cit.  (Note  6)  p.  57. 

13.  Klemperer:    Therap.  d.  Gegenw.,  1911,  lii,  447. 


TABLE    5. — Summary    of   Metabolism    in    Cask    Shown    in    Tablk   4* 

Case   785.     Severe   diabetes.     Weight,  42   kilos.     Male.     Age   at   onset,    15. 
Duration  since  onset  twenty  months. 


Nitrogen    Balance 

Carbohydrate    Balance 

Period 

Urine  and  Feces 

Diet 

Urine 

Diet 

55    days 
Daily  average 

440. 
8.0 

407. 
7.0 

190. 
3.5 

919. 
16.7 

8.9 

.Sugar  present  in  urine  20  days 

• 

Daily  average 

7.8 

8.8 

15.4 

7.5 

Sugar  absent   from  urine  32  days 

Daily  average 

6.4 

0.0 

15.1 

'  Nitrogen  in  feces  estimated  at  10  per  cent,  of  nitrogen  in  diet. 

During  the  fifty-five  days  lie  was  under  my  observation  the  average 
daily  nitrogen  in  the  diet  was  estimated  at  7.0  gm.,  and  in  the  urine 
and  feces  8.0  gm.  The  carbohydrate  in  the  diet  was  16.7  gm.  and  in 
the  urine  3.5  gm.  During  thirty-two  of  the  fifty-five  days,  sugar  was 
absent  from  the  urine  and  on  twenty  days  it  was  present,  although  the 
average  daily  carbohydrate  in  the  diet  was  the  same.  A  study  of  Table 
5  would  suggest  this  being  due  to  the  slightly  lower  nitrogen  intake  on 
the  sugar-free  days.  This  is  not  quite  justifiable,  because  another 
factor  enters  in — namely,  starvation — for  on  several  of  the  thirty-two 
days  the  patient  received  no  food  at  all.  These  starvation  days  evi- 
dently played  an  important  role.  How  very  important  is  shown  by  the 
test  already  recorded  in  Table  4,  where  81  gm.  of  levulose  were 
administered  and  only  7  gm.  carbohydrate  appeared  in  the  urine. 

Is  it  possible  for  the  body  to  store  so  large  a  quantity  of  carbo- 
hydrate as  520  or  even  more  grams  ?  Furthermore  in  what  form  may 
it  be  retained  in  diabetic  patients? 

Nearly  all  experiments  on  the  utilization  of  carbohydrates  in  the 
past  have  been  based  on  the  difference  between  the  carbohydrate  intake 
and  the  carbohydrate  excreted.  Unless  the  amount  of  the  carbo- 
hydrate stored  in  the  body  is  known,  it  is  unjustifiable  to  say  that  the 
carbohydrate  excreted  represents  a  part  of  that  ingested  during  the 
same  twenty-four  hours.  All  data  in  reference  to  the  D :  N  ratio 
are  confused  by  the  possibility  of  stored  carbohydrate.  The  impor- 
tance of  the  storage  of  carbohydrate  thus  becomes  evident. 

The  influence  of  carbohydrate  so  stored  in  the  body  is  also  great. 
Whatever  virtue  the  oatmeal  cure  possesses,  all  agree  that  it  depends 


10 

in  major  part  on  preceding  starvation,  which  has  tended  to  exhaust 
the  carbohydrate  depots  of  the  body. 

Glycogen. — Carbohydrate  is  stored  in  the  body  in  various  ways  but 
most  of  it  is  supposed  to  be  in  the  form  of  glycogen,  and  this  is  about 
equally  divided  between  the  liver  and  the  muscles.  An  old  estimate  of 
Bunge  that  the  body  had  400  gm.  is  roughly  approximated  by  experi- 
ments on  fasting  men  and  professional  athletes  doing  severe  work 
without  food.  This  figure  may  be  taken  as  a  fair  average,  but  there 
are  enormous  variations.  This  statement  is  based  on  glycogen  which 
has  been  shown  to  be  burned;  it  does  not  exclude  the  possibility  of 
some  glycogen  still  remaining  in  the  body,  and  in  fact  Benedict  says : 
"It  would  appear  that  the  estimate  of  400  gm.  of  glycogen  for  the 
content  of  the  body  is  if  anything  too  small  rather  than  too  large." 
Experiments  on  fasting  men  show  that  they  may  burn  from  93  to 
232  gm.  in  the  first  three  days.^*'  ^^  In  diabetic  patients  the  quantity 
of  glycogen  is  universally  considered  to  be  far  below  this  amount,  but 
Frerichs^^  found,  on  puncturing  the  liver  of  two  diabetics,  a  small 
amount  of  glycogen  in  one  and  a  considerable  amount  in  the  other, 
and  Kulz^'^  found  from  10  to  12  gm.  glycogen  in  the  liver  of  a  diabetic 
who  had  been  for  a  long  time  on  a  diabetic  diet.  Examinations  of  the 
tissue  removed  from  the  livers  of  living  diabetic  patients  show  appre- 
ciable quantities  of  glycogen,  and  it  is  the  experience  of  pathologists 
that  the  organs  of  diabetic  patients  contain  more  than  traces  of  glyco- 
gen. It  is  most  unfortunate  that  no  data  exist  which  enable  us  to 
determine  what  this  minimum  is.  It  is  quite  conceivable  that  although 
it  might  be  extremely  small  at  any  one  moment,  a  small  quantity 
might  be  frequently  formed  and  destroyed,  and  the  sum  of  these 
small  quantities  reach  a  substantial  amount  in  twenty-four  hours. 

The  recent  work  of  Helly^®  throws  new  light  on  the  problem.  He 
points  out  the  striking  contrast  between  the  constant  presence  of  gly- 
cogen in  the  liver  of  human  diabetes  and  the  very  small  quantity  which 
is  found  in  the  severe  diabetes  of  depancreatized  dogs,  yet  even  in  the 
latter  the  power  of  the  liver  to  form  or  deposit  glycogen  is  shown 
when  levulose  is  administered.  If  a  milder  form  of  diabetes  is  pro- 
duced in  the  dog  more  glycogen  remains  in  the  body  and  there  is  a 
closer  resemblance  to  human  diabetes ;  whereas  with  total  removal  of 
the  pancreas  there  was  only  0.065  per  cent,  of  glycogen  in  the  liver. 


14.  Benedict:    The  Influence  of  Inanition  on  Metabolism,  Carnegie  Institute 
of  Washington,  1907,  Pub.  77,  p.  464. 

15.  Benedict :   A  Study  of  Prolonged  Fasting,  Carnegie  Institute  of  Washing- 
ton, 1915,  Pub.  203,  p.  251. 

16.  Frerichs :     Ueber   den   Diabetes,   p.   272 ;    cited  by   Nehring  and    Schmoll 
(Note  34).    - 

17.  Kulz:    Arch.  f.  d.  ges.  Physiol.   (Pfliiger's),  1876,  xiii,  267. 

18.  Helly:    Ztschr.  f.  exper.  Path.  u.  Therap.,  1914,  xv,  464. 


11 

• 

On  the  other  hand,  with  partial  removal,  even  though  there  be  8  to  10 
per  cent,  of  sugar  in  the  urine,  there  v^as  0.3  per  cent,  of  glycogen. 
By  microscopic  examination .  so  considerable  a  quantity  as  this 
appeared  small. 

Blood  Sugar. — Sugar  is  also  stored  in  the  body  in  the  form  of 
blood  sugar.  The  normal  quantity  of  sugar  in  the  blood  of  healthy  indi- 
viduals varies  between  0.07  and  0.11  per  cent,  and  for  convenience  in 
calculations  may  be  considered  0.1  per  cent.  This  rises  quickly  after  a 
meal  rich  in  carbohydrates,  but  soon  falls  to  its  former  level.  In  fifty- 
five  observations  on  fifteen  of  our  diabetic  patients  the  percentage  of 
blood  sugar  varied  from  0.12  to  0.36  per  cent.  But  the  blood  of  these 
diabetic  patients  does  not  behave  like  that  of  normal  individuals  fol- 
lowing the  ingestion  of  food.  It  is  true  that  the  percentage  of  sugar 
rapidly  increases  following  a  carbohydrate  meal,  but  it  does  not  as 
rapidly  fall,  and  in  my  own  experience  most  diabetic  patients,  even 
after  prolonged  fasting,  show  values  for  blood  sugar  which  are  far 
above  normal.  Certain  types  of  diabetic  patients — namely,  those  with 
disease  of  the  kidneys — are  especially  prone  to  maintain  high  per- 
centages of  sugar  in  the  blood  for  many  days  after  their  urines  have 
become  sugar-free.  It  is  impracticable  to  consider  that  the  percentage 
of  blood  sugar  is  maintained  independently  of  the  other  tissues  in  the 
body — first,  because  the  percentage  is  so  unstable ;  second,  because 
there  is  no  constant  relation  between  the  sugar  in  the  blood  serum  and 
the  sugar  in  the  total  blood,  and  third,  because  the  capacity  of  the 
blood  for  storage  of  sugar  is  so  slight.  If  we  assume  an  individual 
of  70  kilos  body  weight  and  consider  that  7  per  cent,  of  the  weight  is 
made  up  of  blood,  we  have  4.9  kilos  of  blood  with  a  normal  sugar 
content  of  0.1  per  cent.  This  would  amount  to  4.9  gm.,  even  taking 
the  highest  for  the  normal  individual,  and  should  we  take  the  highest 
figures  we  have  encountered  even  after  the  administration  of  food 
with  our  diabetic  patients,  namely  0.36  per  cent.,  the  total  quantity  of 
sugar  stored  in  the  blood  would  not  be  far  from  18  gm. — a  trifle  more 
than  a  half  ounce. 

Falta^''  has  called  attention  to  the  slow  return  of  the  blood  of  dia- 
betic patients  to  its  former  sugar  level,  and  emphasizes  this  point  as  of 
fundamental  importance  in  diabetes.  He  points  out  that  the  dis- 
turbance of  blood  sugar  utilization  is  not  the  same  as  the  disturbance 
of  glycogen  formation  for  the  blood  sugar  regulation  may  be  inter- 
fered with  when  the  glycogen  formation  is  not. 

Kleiner  and  Meltzer-°  have  also  beautifully  shown  this  same  dif- 
ference in  depancreatized  dogs.     Whereas,  following  the  injection  of 


19.  Falta:    Med.  Klin.,  1914,  x,  9. 

20.  Kleiner  and  Meltzer :    Proc.  Soc.  for  Exper.  Biol,  and  Med.,  1914.  xii,  58. 


12 

4  gm.  dextrose  per  kilo  weight,  the  sugar  in  the  blood  of  normal  dogs 
increases  fourfold — namely,  from  0.20  per  cent.,  to  0.79  per  cent. — 
and  that  of  depancreatized  dogs  threefold — from  0.38  per  cent,  before 
to  1.19  per  cent,  after  the  injection — the  blood  sugar  of  the  former 
returned  nearly  to  normal  at  the  end  of  an  hour  and  a  half,\vhile 
the  diabetic  dogs  even  then  showed  0.86.  It  is  significant  that  in  these 
experiments  the  quantities  of  sugar  excreted  in  the  urine  were  prac- 
tically the  same.  Interesting  as  these  figures  are  from  this  point  of 
view,  from  another  they  are  still  more  interesting.  It  is  impossible  to 
account  for  all  the  sugar  ingested  by  adding  together  the  sugar  found 
in  the  blood  and  that  in  the  urine.  Where  did  the  sugar  go  ?  You  may 
say  it  was  burned,  and  this  possibility,  though  not  probability,  must  be 
admitted  in  the  normal  animal,  but  no  one  would  contend  this  to  be 
wholly  the  case  in  the  depancreatized  animal. 

At  the  Nutrition  Laboratory  we  have  been  able  to  carry  these 
experiments  to  their  logical  conclusion,  for  we  have  had  the  oppor- 
tunity to  determine  the  respiratory  quotient  following  the  administra- 
tion of  levulose  to  severe  diabetics.  In  Table  20  will  be  found  a 
report  of  the  effect  of  levulose  when  administered  to  severe  diabetic 
patients  in  amounts  to  2.51  gm.,  2.42  gm.  and  1.95  gm.  per  kilogram 
body  weight.  In  the  first  and  third  cases  there  was  no  increase  in 
the  respiratory  quotient.  A  considerable  portion  of  the  levulose  was 
probably  excreted  in  the  first  case,  but  in  the  third  little  or  none.  The 
explanation  of  this  difference  in  behavior  in  the  storage  of  levulose  is 
probably  that  the  first  patient  had  not  fasted  beforehand  and  that  the 
third  had  been  on  a  low  carbohydrate  diet  for  a  long  time ;  this  is  con- 
firmed by  the  second  case,  in  which  also  little  of  the  levulose  was 
excreted  when  administered  following  a  period  of  strict  dieting.  An 
increase  in  the  respiratory  quotient  occurred  in  this  case,  but  it  was  so 
slight  as  to  preclude  any  considerable  quantity  of  the  sugar  having 
been  burned.  It  should  also  be  recorded  that  in  all  the  cases  the 
levulose  was  given  at  one  time  and  not  spread  out  through  the  twenty- 
four  hours,  as  in  Klemperer's  test.  This  gives  added  emphasis  to  the 
possibility  of  the  presence  of  an  empty  storehouse  for  carbohydrate 
in  the  body.  I  also  have  evidence  that  the  gradual  administration  of 
carbohydrates  is  of  little  value,  provided  the  body  is  not  prepared  to 
retain  it.  Following  etherization  a  patient  (Case  808),  while  fasting 
for  the  first  twenty-four  hours  was  sugar-free,  but  on  the  next  day, 
although  only  2  gm.  carbohydrate  per  hour  were  administered,  he 
excreted  practically  all  of  it,  although  formerly  his  tolerance  amounted 
to  50  gm.  carbohydrate. 

The  small  amount  of  glycogen  and  the  still  smaller  quantity  of 
blood  sugar  represent  an  amount  of   carbohydrate   far  too  low   to 


13 

account  for  the  phenomena  above  described  in  diabetes.  Other  sources 
for  storage  of  sugar  in  the  body  must  be  sought,  as  has  been  empha- 
sized by  Ivar  Bang.  If  we  should  assume  tliat  the  percentage  of  sugar 
in  the  blood  was  the  same  for  all  the  fluid  in  the  body,  certain  amounts 
of  sugar  might  be  stored  in  this  manner.  While  such  an  assumption  is 
not  wholly  justifiable,  it  has  some  basis,  for  we  know  that  sugar 
exists  in  the  spinal  fluid  of  diabetics,  as  well  as  in  other  fluids.  In 
normals  Dr.  Jacobson  tells  me  that  he  has  not  found  it  so  closely  to 
follow  the  blood,  but  the  opposite  was  true  in  his  cases  of  diabetes 
mellitus.  It  gets  into  the  blood  and  cannot  seem  to  get  out.  Notable 
percentages  of  sugar,  not  very  different  from  those  in  the  blood,  have 
been  found  in  pleuritic  and  ascitic  fluids,  and  Husband  found  even  0.7 
per  cent,  in  the  amniotic  fluid.  There  is  some  doubt  about  its  presence 
in  sweat,  but  we  do  have  a  record  of  sweet  tears.  Yet  granted  that 
the  assumption  is  correct,  we  cannot  increase  our  storage  capacity  very 
much  that  way.  For  example,  assuming  the  total  quantity  of  fluid  in 
the  body  as  60  per  cent,  of  the  body  weight  of  70  kg.,  we  have  42  kg. 
of  body  fluid,  from  which  we  must  deduct  4.9  kg.  already  reckoned  as 
blood.  This  leaves  us  a  remainder  of  37.1  kg.  of  fluid  in  the  body,  and 
using  the  highest  figure^O.36  per  cent. — for  blood  sugar  which  we 
have  encountered,  the  quantity  of  sugar  in  this  mass  of  fluid  would 
be  only  133  gm.  This  is  not  enough  relatively  to  explain  Kleiner's 
and  Meltzer's  experiment. 

Another  source  for  the  formation,  although  perhaps  not  for  the 
storage  of  carbohydrate  in  the  body,  has  long  been  recognized  in  pro- 
tein. The  close  connection  which  is  maintained  between  protein  and 
carbohydrate  in  diabetes  would  make  a  clinician  with  modest  chemical 
knowledge  seek  for  some  combination  of  carbohydrate  in  the  protein 
molecule — some  arrangement  by  which  a  portion  of  the  sugar  molecule 
could  be  stored  in  protein  or  given  up  as  occasion  arises,  just  as  water 
is  squeezed  out  of  a  sponge.  Good  chemists,  and  I  have  asked  many, 
assure  me  that  even  with  glucoproteins  sugar  can  be  extracted  from 
the  protein  molecule  only  when  the  molecule  itself  is  disintegrated. 
The  large  quantity  of  movable  protein  and  fat  in  the  body  suggests  a 
large  carbohydrate  reservoir,  too.  Few  realize  how  large  this  quantity 
of  movable  protein  is.  It  has  been  shown  by  Albert  Miiller-^  that 
by  overfeeding,  210  gm.  of  nitrogen,  the  equivalent  of  1260  gm.  of 
body  protein,  in  turn  the  equivalent  of  6.3  kilos  of  muscle  tissue,  can  be 
retained  by  the  body,  and  conversely,  it  has  been  shown  by  Benedict^^ 
that  even  more — 277  gm.— can  be  removed.  This  movable  protein 
amounts  to  about  one-third  of  the  total  body  protein.     The  readiness 


21.  Miiller:    Zenlralbl.   f.   d.   Ges.   Phvsiol.   u.   Path.  d.   Stoffswechs.,   1911,  vi. 
617. 


14 

with  which  fat  can  be  increased  and  decreased  in  the  body  is  univer- 
sally recognized. 

Although  we  are  not  allowed  to  say  that  carbohydrate  can  be 
extracted  from  the  protein  molecule,  leaving  it  intact,  we  do  know 
that  in  severe  diabetes  sugar  can  be  formed  out  of  protein.  Professor 
Lusk-^  has  demonstrated  this  in  completely  depancreatized  dogs  and 
in  his  now  famous  diabetic  patient,  3.65  gm.  dextrose  appeared  in  the 
urine  for  each  gram  of  nitrogen  therein  contained.  This  represents 
approximately  60  gm.  dextrose  for  each  100  gm.  protein.  If  we 
should  assume  that  in  diabetic  patients  there  were  1,200  gm.  movable 
protein,  this  would  furnish  a  possible  source  of  720  gm.  more  of  car- 
bohydrate. 

Unfortunately  one  cannot  be  sure  that  in  the  disintegration  of  the 
protein  molecule  the  nitrogen  and  carbohydrate  leave  the  body  hand  in 
hand.  As  a  rule,  the  nitrogen  loiters  behind,  greatly  to  our  annoyance 
in  estimating  the  source  of  the  sugar  in  the  urine.  Mendel  and 
Lewis^^  have  recently  shown  that  this  delay  was  increased  if  either 
indigestible  substances  or  cotton  seed  oil  form  a  prominent  part  of 
the  diet — just  the  sort  of  foods  which  our  diabetic  patients  eat.  Con- 
sequently if  an  attempt  to  determine  the  quantity  of  carbohydrate  from 
protein  (dextrose  nitrogen  ratio  D:  N)  is  made,  this  irregularity  in  the 
excretion  of  nitrogen  must  be  considered.  When  one  adds  to  this 
difficulty  that  of  determining  what  share  the  quantity  of  residual 
carbohydrate  in  the  body  bears  to  the  total  sugar  excreted,  and  when 
one  considers  that  even  under  an  absolutely  uniform  diet  of  1,000  gm. 
meat  and  1,750  c.c.  fluid  intake  for  fifteen  days  Naunyn^*  found 
variation  of  sugar  excretion  from  12  gm.  to  43  gm.,  and  frequently 
of  100  per  cent.,  I  feel  very  modest  about  asserting  that  my  patients 
are  producing  any  given  quantity  of  sugar  for  each  gram  of  nitrogen 
excreted.  Naunyn  says  that  these  spontaneous  variations  may  reach 
even  70  gm.  Kulz  has  emphasized  this  same  point.  If  under  ideal  con- 
ditions for  fifteen  days  such  variations  exist,  it  behooves  one  to  accept 
with  caution  reported  D :  N  ratios  for  a  period  of  a  few  days  as  being 
of  value  or  to  base  arguments,  as  is  sometimes  done,  on  the  D :  N  ratio 
of  single  isolated  days  selected  from  a  series.  In  the  tables  of  Rumpf, 
Allard,  Hesse,  and  some  of  Liithje's,  D:  N  ratios  are  recorded  which 
Professor  Lusk  and  I  would  feel  indicated  a  far  larger  per  cent,  of 
carbohydrate  coming  from  protein  than  is  actually  the  case.  It  is 
arbitrary  selection  to  pick  from  these  tables  all  ratios  above  3.65 :  1 
and  say  they  are  wrong  and  to  class  the  remainder  as  correct.     It  is 


22.  Mandel  and  Lusk:    Deutsch.  Arch.  f.  klin.  Med.,  1904,  Ixxxi,  472. 

23.  Mendel  and  Lewis:    Jour.  Biol.  Chem.,  1913-14,  xvi,  pp.  19,  37. 

24.  Naunyn:  Des  Diabetes  Melitus,  1906,  p.  183. 


15 

furthermore  remarkable  that  with  fasting  all  IJ :  N  ratios  cease  to 
exist.  It  is  also  hard  to  understood  how  a  patient  one  day  fails  to 
burn  the  protein  of  an  ox,  but  the  next  day  burns  his  own  body  protein 
with  ease.  Fasting  diabetics  will  afford  unusual  opportunities  to  study 
this  point.  As  a  rule,  the  high  D :  N  ratios  are  found  when  the  nitrogen 
excretion  is  high,  and  it  may  be  tiiat  to  produce  these  high  ratios  large 
quantities  of  protein  may  be  required. 


VoluTue 

Sugar 

Nove-mber 

Dece-mber                 I 

e.e. 

em. 

23 

24 

25 

26 

Z7 

Z8 

29  1 

50 

1 

2 

3 

4 

5 

6    1 

1 

2  150 

zioo 

2050 
2000 
1950 
1900 
1850 
1800 
17  50 
1700 
1650 
1600 
1550 
1500 
14  50 
1400 
1350 
1300 
1250 
1200 
1150 
MOO 
1050 
lOQO 

42 
40 

38 
36 
34 
32 
30 
28 
26 
24 
22 
;   20 
18 
16 
14 
12 
10 

I 

\ 

\ 

/ 

\ 

N 

/ 

\ 

1 

/ 

\ 

/ 

1 

\ 

/ 

\ 

/ 

\ 

1^ 

\ 

I 

ll 

V 

j 

\ 

1 

\ 

' 

1' 

1 

ll 

1 

1 

1/ 

1' 

T 

L 

1 

/ 

\ 

i 

i^ 

V, 

1 

11 

f 

V 

\ 

f 

\ 

\ 

/ 

< 

/ 

1, 

1 

> 

>.. 

J 

r 

J 

1/ 

\ 

1 

1 

R 

/ 

> 

\' 

/ 

j 

\ 

/ 

^ 

/ 

1 

If 

Y 

/ 

1 

1 

/ 

'\ 

/ 

1 

\ 

1 

1 

_ 

__ 

Chart  illustrating  variations  in  excretions  of  urine  and  sugar  of  a  severe 
diabetic  on  a  constant  diet  (from  Naunyn).  Diet  constant  1,000  gm.  meat, 
1,750  c.c.  fluid.  Line  composed  of  dots  and  dashes  indicates  c.c.  urine  in  twenty- 
four  hours ;  continuous  line,  gm.  sugar  in  twenty-four  hours. 


The  small  part  which  the  blood  plays  in  the  storage  of  carbo- 
hydrate has  been  pointed  out.  This  is  peculiarly  unfortunate  because 
one  would  hope  from  the  percentage  of  sugar  in  the  blood  to  derive 
some  knowledge  of  the  course  of  metabolism  in  dis.betes.  As  if  to 
emphasize  the  independence  of  the  metabolism  to  the  content  of  sugar 
in  the  body,  I  submit  at  this  point  Table  6,  which  gives  the  respira- 
tory quotients  obtained  upon  individuals  whose  blood  sugar  was  deter- 


16 


mined  at  the  time  of  the  test,  reserving  discussion  of  the  same  to  a 
later  portion  of  the  paper. 

TABLE   6. — The   Blood    Sugar   and    Respiratory    Quotient    in    Severe 

Diabetes  ^ 


Case   No. 


806 
806 
786 
806 
765 
810 
806 
765 
765 
714 
786 
765 

773 
773 

746 
746 
786 


Condition 


Fasting     

Fasting     

Fasting     

After  potato  (60  gm.  carb.) 

I'asting     

Fasting     

After  one  egg  and  200  gm.  vegetables 

Fasting     

Fasting 

Fasting 

After  oatmeal    (60  gm.   carb.) 

After  oatmeal  (10  gm.  carb.)  and  potato  (48  gm 
carb.). 

Fasting     

After  oatmeal    (80  gm.  carb.) 

Fasting     

After  oatmeal    (40-60   gm.   carb.) 

After  oatmeal   (120   ±   gm.  carb.) 


Per  cent,  of 

Sugar    in 

Blood 


0.12 
0.14 
0.17 
0.18 
0.18 
0.19 
0.19 
0.23 
0.24 
0.25 
0.25 

0.26 
0.27 
0.30 
0.30 
0.36 
0.36 


R.   Q. 


0.71 
0.68 
0.69 
0.69 
0.74 
0.72 
0.72 
0.76 
0.73 
0.78 
0.74 

0.74 
0.70 
0.70 
0.70 
0.74 
0.83 


IV.    THE    RESPIRATORY    METABOLISM    AND    ITS    RELATION    TO    THE 
UTILIZATION    OF    CARBOHYDRATE 

An  examination  of  the  composition  of  the  carbohydrate  molecule 
will  show  that  it  contains  sufficient  oxygen  to  unite  with  all  the  hydro- 
gen present.  Consequently,  for  each  volume  of  oxygen  used  in  the 
oxidation  of  carbohydrate  a  volume  of  carbon  dioxid  will  be  produced. 
The  relation  which  the  volume  of  carbon  dioxid  produced  bears  to  the 
oxygen  required  for  the  oxidation  of  a  food  constitutes  its  respiratory 
quotient.  It  is  obvious,  therefore,  that  the  respiratory  quotient  of 
such  a  carbohydrate  as  glucose  (CeHjoOe)  is  1.  It  matters  not 
whether  the  oxidation  takes  place  rapidly  outside  of  the  body  in  a 
flame,  or  less  obtrusively  in  the  body  during  twenty-four  hours.  Pro- 
tein, on  the  other  hand,  does  not  contain  sufficient  oxygen  for  the 
hydrogen  atoms  contained  in  its  molecule.  As  a  result,  in  the  burning 
of  protein,  oxygen  must  be  used  not  only  for  the  carbon  in  the  mole- 
cule, but  for  the  hydrogen  as  well.  The  denominator  of  the  fraction  is 
thus  increased,  and  the  respiratory  quotient  of  protein  must  be  less  than 
1,  and  is  0.81.  The  protein  molecule  is  made  up  of  many  component 
parts  and  while  the  respiratory  quotients  of  these  parts  vary  greatly, 
yet  for  protein  as  a  whole  the  foregoing  quotient,  0.81,  holds.  With 
fat  a  similar  condition  exists  to  that  in  protein,  only  there  is  still  more 
hydrogen  present  to  require  oxygen,  so  that  the  amount  of  oxygen 
necessary  for  the  combustion  of  fat  is  still  greater,  and  as  a  result  the 
respiratory  quotient  falls  to  0.70.  The  respiratory  quotient  of  alcohol 
is  still  lower,  namely,  0.67.     Beta-oxybutyric  acid,  which  can  be  taken 


17 

as  the  chief  one  of  the  group  of  acid  bodies  formed  in  diabetes,  has  a 
respiratory  quotient  of  0.89,  diacetic  acid  has  a  respiratory  quotient 
of  1.00,  and  acetone  of  0.75,  so  that  one  will  not  go  far  astray  to 
take  0.89  as  a  common  respiratory  quotient  for  these  three  acid  bodies. 
The  respiratory  quotient  of  an  individual  can  be  determined  by 
measurement  of  the  quantity  of  carbon  dioxid  exhaled  and  the  oxygen 
absorbed.  When  this  is  done,  information  is  obtained  concerning  the 
character  and  total  amount  of  the  combustion  taking  place  in  the  body. 
Since  the  urinary  nitrogen  gives  us  a  definite  idea  of  the  quantity  of 
protein  metabolized,  if  we  calculate  what  this  represents  and  subtract 
it  from  the  total  material  burned,  we  have  left  the  combustion  derived 
simply  from  fat  and  carbohydrate.  When  the  respiratory  quotient  of 
fat  and  carbohydrate,  as  well  as  that  of  the  individual,  is  known,  it  is 
possible,  by  computation,  to  determine  the  share  which  these  two 
variables  have  taken  in  the  total  metabolism. 

TABLE    7. — The    Respiratory    Quotient    (R.    Q.)   of    a    Food    is    Obtained 

BY    Dividing   the   Volume   of    Carbon    Dioxid   Produced   During 

Its    Oxidization    by   the   Volume   of   Oxygen    Absorbed 


Volume  of  Oxygen  Absorbed 


Carbohydrate:  CoHiaOe  +  6  O2  =  6  CO2  +6  H2O 

Oxygen  is  required  for  oxidation  of  carbon  alone 
6  CO2  produced 

6  O2     I'.bsorhed 
Fat:  CsiHioiOg 

Oxygen   required   for  carbon  and   a  large  quantity   of   hydrogen. 

Protein :    Occupies    an    intermediate    position 

Alcohol:  CoHeO    

B eta-0 xybiityric  acid :   C4H8O3 

Diacetic  acid:   C^HeOs 

Acetone:  CaHeO    


R.   Q. 


1.00 


0.71 
0.81 
0.67 
0.89 
1.00 
0.75 


The  Technic  of  the  Determination  of  the  Exchange  of  Carbon 
Dioxid  and  Oxygen  in  Man. — Two  types  of  apparatus  are  employed  to 
learn  the  exchange  of  carbon  dioxid  and  oxygen  in  man ;  the  calorime- 
ter and  respiration  apparatus.  In  the  closed  chamber  of  the  calorime- 
ter the  oxygen  admitted  and  the  carbon  dioxid  withdrawn  can  be 
accurately  determined  in  periods  usually  of  one  hour's  duration,  but 
it  is  better  to  take  the  average  of  the  results  obtained  in  three  succes- 
sive periods.  Occasionally  each  period  may  be  shortened  to  three- 
quarters  of  an  hour,  exceptionally  to  half  an  hour,  but  tlie  large  size 
of  the  calorimeter  increases  the  chances  for  error.  The  calorimeter  is 
cumbersome,  expensive  to  construct  and  to  maintain,  and  the  length 
of  the  experiment  is  not  only  disagreeable  to  the  patient,  but  disad- 
vantageous in  studying  the  results  of  rapid  changes  in  the  metabolism, 
which  are  desirable  in  a  study  of  the  utilization  of  foods.  On  the  other 
hand,  the  respiratory  apparatus  is  advantageous  because  the  exchange 


18 

of  gases  can  be  determined  during  short  periods  of  fifteen  minutes. 
It  is  disadvantageous,  however,  because,  the  periods  being  so  short, 
errors  at  the  beginning  and  end  of  the  periods  are  magnified  and 
because  the  individual  must  breathe  through  a  nosepiece  or  mouthpiece, 
and  this  introduces  an  abnormal  state.  Unfortunately,  in  each  form 
of  apparatus,  the  error  of  a  leak  falls  chiefly  on  the  oxygen,  because 
the  patient  and  the  apparatus  constitute  a  closed  circuit,  and  any 
diminution  in  gas  in  this  circuit  must  be  offset  by  the  addition  of 
oxygen.  A  more  troublesome  source  of  error  and  one  difficult  to 
avoid  arises  from  the  possibility  of  the  patient  exhaling  carbon  dioxid, 
which  has  previously  accumulated  in  the  body,  at  a  more  rapid  rate 
than  corresponds  with  the  oxygen  inhaled.  The  patient  is  said  to 
"pump  out"  carbon  dioxid.  There  is  also  another  error  due  to  carbon 
dioxid  which  is  lost  by  cutaneous  respiration,  and  it  has  been  calcu- 
lated that  this  would  lower  the  'quotient  0.01  to  0.15. 

Many  pitfalls,  therefore,  lurk  in  the  determination  of  the  respira- 
tory exchange  of  an  individual.  The  carbon  dioxid  is  the  more  easily 
estimated  of  the  two  gases  and  in  early  experiments  on  metabolism 
investigators  attempted  this  alone.  The  determination  of  oxygen  is 
far  more  difficult.  Hence,  in  dealing  with  the  respiratory  quotient, 
which  depends  on  the  relation  of  these  two  determinations  to  each 
other,  one  treads  on  very  dangerous  ground,  and  all  statements  regard- 
ing the  respiratory  quotient  of  individuals  must  be  accepted  with 
caution.  The  general  picture  of  the  respiratory  quotient  in  an 
individual  is  far  more  valuable  as  a  guide  to  his  true  metabolism  if 
based  on  several  experiments  than  is  the  result  of  a  single  experiment. 
Similarly,  it  is  probably  safer  to  average  the  results  of  a  series  of  cases 
than  to  attach  too  much  importance  to  figures  obtained  in  one. 

-The  Respiratory  Quotient  of  the  Normal  Individual. — The  respira- 
tory quotient  of  the  normal  individual  is  best  determined  at  least 
twelve  hours  after  a  meal.  It  has  been  shown  that  if  this  rule  is  not 
followed  the  composition  of  the  meal  will  have  a  marked  influence  on 
the  result.  Under  these  circumstances  the  respiratory  quotient  of 
normal  individuals  does  not  greatly  vary.  Benedict,  Emmes,  Roth 
and  Smith^^  working  at  the  Nutrition  Laboratory  of  the  Carnegie  Insti- 
tution, have  studied  the  basal  gaseous  metabolism  for  89  men  and  68 
women  and  their  average  results  are  shown  in  Table  8. 

I  would  call  attention  to  the  slight  difference  existing  between  the 
respiratory  quotient  of  men  and  women — 0.83  and  0.81.  I  have  also 
incorporated  the  heat  production,  calculated  from  the  oxygen  intake, 
which  was  approximately  25  calories  per  kilogram  per  twenty-four 
hours.     This  latter  figure  is  lower  than  we  are  apt  to  consider,  but  it 


25.  Benedict,  Emmes,  Roth  and  Smith:    Jour.  Biol.  Chem,  1914,  18,  139. 


19 

should  be  remembered  that  it  is  based  on  fasting  periods  when  the 
patient  is  purposely  endeavoring  to  be  quiet.  It  would  be  absolutely 
wrong,  from  such  determinations  covering  periods  of  fifteen  minutes, 
or  even  a  few  hours,  to  draw  conclusions  on  the  total  heat  production 
for  the  day.  In  illustration  of  the  method  and  at  the  same  time  of 
the  difficulties  of  determining  the  respiratory  quotient  of  normal 
individuals  I  give  the  figures  in  my  own  case  (Table  9). 

TABLE    8. — Respiratory    Quotient    and    Total    Metabolism    of    Normal 
Individuals   at   Rest   at   Least   Twelve    Hours   After   the   Last   Meal 


Individuals 

R.   Q. 

Calories  per   Kilo 
per    24    Hours 

89    men 
68  women 

Average  =  0.83 
Average  =  0.81 

2S.S 
24.9 

TABLE   9. — Respiratory    Quotient    of   a    Normal    Person 
Normal  individual  (E.  P.  J.)  fasting  experiment.   December  23,  1914.   Weight, 
64.9  l<ilos.     Height,  177.8  centimeters. 


Duration 

CO. 

Per    Min. 
c.c. 

Per    Min. 
c.c. 

R.  Q. 

Calories  per 

Min. 

Sec. 

kilo,    per 
24   hours 

IS 
1-1 
IS 

6 

S9 

0 

152 

ISO 
153      , 

192 
194 
196 

0.80 
0.77 
0.78 

20.40 
20.51 

20.77 

Average 

=  0.78 

Naturally  I  took  the  greatest  possible  pains  to  be  quiet  and  breathe 
in  a  normal  manner,  but  it  will  be  seen  that  whereas  the  values  for 
the  carbon  dioxid  of  themselves,  and  of  oxygen  for  themselves  vary 
to  an  extremely  small  degree  from  period  to  period,  yet  they  differ 
sufficiently  to  make  a  considerable  variation  in  the  respiratory  quotient. 
This  experiment  emphasizes  the  possibilities  for  error  in  the  deter- 
mination of  the  respiratory  quotient  even  under  most  favorable  cir- 
cumstances. 

The  respiratory  quotient  of  individuals  fasting  for  long  periods  is 
well  exemplified  by  the  studies  made  by  Benedict^^  on  a  man  who 
went  thirty-one  days  without  food.  These  are  illustrated  in 
Tables  10  and  11. 

It  will  be  seen  that,  prior  to  the  experiment,  the  respiratory  quotient 
differed  little  from  that  of  the  group  of  normal  individuals  above  men- 
tioned. With  the  withdrawal  of  all  food  the  respiratory  quotient  fell, 
and  after  the  fifth  day  reached  a  point  which  Magnus-Levy-*'  has  said 


26.  Magnus-Levy:    Ztschr.  f.  klin.  Med.,  1905,  Ivi,  83. 


20 

theoretically  represents  the  quotient  which  is  obtained  when  the 
metabolism  consists  of  85  per  cent,  of  fat  and  15  per  cent,  of  protein, 
namely,  0.72.  In  other  words,  five  days  of  starvation  removed  the 
last  discernible  influence  of  carbohydrate  remaining  stored  in  the 
body,  and  the  individual  lived  wholly  on  body  fat  and  body  protein: 
It  is  possible  to  discover  how  much  fat  and  how  much  carbohydrate 
take  part  in  the  metabolism. 

TABLE   10. — The   Respiratory   Quotient   of   a   Man    During   a   Prolonged 

Fast 


Preliminary 
Period 


Period 
ot 


Fast 


After 
Period 


Fourth  day  before  fast. 
Third  day  before  fast. . 
Second  day  before  fast. 
First  day  before  fast. . . 


Days  1 — 5  of  fast. .. 
Days  6 — 31  of  fast. 
Days  6 — 31,  early  a. 


Second  day  after  breaking  fast* 
Third  day  after  breaking  fast*.. 


0.81 
0.89 
0.89 
0.82 

0.77  (Avge.) 
0.72  (Avge.) 
0.73  (Avge.) 

0.78 
0.94 


33 

32 
29 
21 

26 
23 
23 

25 
27 


*  Twelve  hours  after  food. 

TABLE    11. — Quantities    of   Protein,    Carbohydrate    and    Fat    Oxidized    by    Fasting 

Man   at   Nutrition   Laboratory  * 


Period 

of 

Fast 

R.  Q. 

Quantities   Oxidized 

Calories  per 
kilo,  per 
24  hours 

•   Actual 

Non-Prot. 

Protein 
gm. 

Carb. 
gra. 

Fat 
gm. 

1st  Day 
2d   Day 
3d  Day 
4th  Day 
5th  Day 
6th  to  31st 
Day   Average 

0.78 
0.75 
0.74 
0.75 
0.76 
0.72 

0.76 
0.74 
0.74 
0.71 
0.72 
0.70 

43 
50 
68 
71 
63 
53 

69 
42 
39 

4 
15 

Ot 

135 
142 
130 
136 
133 
114 

30 
30 
29 
28 
■28 
26 

•Determined  from  the  Daily  Metabolism,  the  Urinary  Nitrogen  and  the  Calculated  Non- Protein  R.  Q. 
t  Actually  a   total   of    32    gm.    carb.    were   burned  during    the    sixth    to    thirteenth    day,    inclusive,    and 
later  none. 


Knowing  the  nitrogen  in  the  urine,  one  can  calculate  the  amount  of 
oxygen  employed  by  the  body  for  the  oxidation  of  the  protein^^  which 
it  represents,  and  correspondingly,  the  amount  of  carbon  dioxid 
given  off  can  be  determined.  If  we  subtract  these  computed  figures 
from  the  total  carbon  dioxid  and  oxygen  obtained  by  direct  experiment, 
we  have  left  the  carbon  dioxid  produced  by  the  non-protein  metabolism 
in  the  body,  and  the  relation  of  the  two  gives  the  non-protein  respira- 


27.  In  estimating  the  quantity  of  body  protein  burned  from  nitrogen  in  the 
urine  the  equivalent  6.00  is  employed  instead  of  6.25. 


21 

tory  quotient.  In  a  useful  table  constructed  by  Lusk,^®  the  percentage 
of  carbohydrate  and  of  fat  for  any  given  non-protein  respiratory 
quotient  between  70  and  100  can  be  calculated.  On  this  basis  it  was 
shown  that  Benedict's  fasting  man  burned  either  no  carbohydrate  or 
only  a  trace  after  the  sixth  day.  When  the  respiratory  quotient  of 
this  man  was  0.73  on  the  seventh  day  it  represented  a  nonprotein 
respiratory  quotient  of  0.70  and  no  carbohydrate  was  burned.  A 
respiratory  quotient  of  0.74  gave  a  nonprotein  respiratory  quotient 
of  0.71,  which  represents  the  oxidation  of  3.8  gm.  of  carbohydrate; 
a  respiratory  quotient  of  0.76  gave  a  nonprotein  respiratory  quotient 
of  0.72,  which  is  evidence  that  15  gm.  carbohydrate  were  burned. 

Respiratory  Quotient  in  Normal  Individuals  after  Food. — The 
respiratory  quotient  following  the  ingestion  of  food  is  shown  well 
by  the  fasting  man  at  the  Nutrition  Laboratory  for  the  periods  before 
fasting  commenced.  It  will  be  seen  that  twelve  hours  after  food  it 
varied  from  0.81  to  0.89  in  the  four  days.  Similarly,  following  the 
termination  of  the  fast,  the  respiratory  quotient  rose,  indicating  the 
combustion  of  large  quantities  of  carbohydrate. 

An  experiment  was  performed  on  myself  which  was  comparable 
to  those  later  carried  on  with  the  diabetic  patients  when  tests  were 
made  of  the  influence  of  food  on  their  metabolism.  The  changes  in 
my  own  respiratory  quotient  following  the  ingestion  of  60  gm.  of 
carbohydrate  in  the  form  of  oatmeal  are  given  in  Table  12. 

It  will  be  seen  that  the  respiratory  quotient  within  an  hour  rose 
some  eight  points  after  eating  60  gm.  of  carbohydrate  in  the  form  of 
oatmeal.  It  has  been  calculated  that  if  48  gm.  carbohydrate  are 
burned  in  twenty-four  hours  at  the  rate  of  2  gm.  of  carbohydrate  each 
hour  continuously  for  the  twenty-four  hours,  the  respiratory  quotient 
would  rise  3  points — in  other  words,  would  be  about  0.75  instead  of 
0.72,  which  is  a  fat-protein  quotient.  I  wish  to  emphasize  the  change 
in  respiratory  quotient  of  only  3  points  when  approximately  48  gm. 
carbohydrate  are  burned  at  the  rate  of  2  gm.  carbohydrate  per  hour 
per  day,  and  the  rise  of  8  points  following  directly  on  the  ingestion  of 
60  gm.  carbohydrate.  The  continuous  combustion  of  small  portions  of 
carbohydrate  amounts  to  the  combustion  of  a  considerable  quantity  of 
carbohydrate  during  the  whole  day,  and  yet  it  will  raise  the  respiratory 
quotient  very  little.  The  combustion  of  24  gm.  of  carbohydrate  at  the 
rate  of  1  gm.  per  hour  could  scarcely  be  detected  with  our  present 
methods,  and  yet  a  tolerance  for  24  gm.  carbohydrate  is  relatively  a 
high  tolerance  when  one  is  dealing  with  serious  cases  of  diabetes. 

The  Respiratory  Quotient  in  Diabetes. — In  mild  cases  of  diabetes, 
when  the  urine  is  free  from  sugar  and  the  carbohydrate  in  the  diet 


28.  Williams,  Riche  and  Lusk :  Jour.  Biol.  Chem.,  1912,  xii,  357. 


22 

large,  the  respiratory  quotient  differs  little  from  that  of  normal  indi- 
viduals. The  respiratory  quotient  of  these  same  mild  cases  of  diabetes 
will  be  lowered  by  fasting  or  by  the  withdrawal  of  carbohydrate,  as 
just  shown  in  the  case  of  the  normal  fasting  man.  Undoubtedly  the 
limited  quantity  of  carbohydrate  in  the  diet  in  cases  of  severe  diabetes 
is  responsible  to  a  large  degree  for  the  low  respiratory  quotient  which 
such  patients  show.     Magnus-Levy  called  attention  to  this,  and  so 

TABLE    12. — Metabolism    of    a    Normal    Individual    After    Food 

Weight,   64.9   kilos.      Height,    177.8   cm. 


Date 

Condition 

CO.. 

Per   Min. 
c.c. 

O, 

Per    Min. 
c.c. 

R.  Q. 

Calories  Per 
Kilo.    Per 
24   Hours 

9/  9/14 
9/10/14 
9/30/14 

1-2     hours     after 

breakfast 
1-2     hours     after 

breakfast 
9    a.    m.,    fasting 

205 
192 
159 

241 
237 
194 

0.85 
0.81 
0.82 

26 
25 
21 

10:30  a.  m.,  after 
60  gm.  carb.  as 
oatmeal 

189 

212 

0.90 

23 

12/23/14 

8    a.    m.,    fasting 

152 

194 

0.78 

21 

1    p.    m.,    fasting 

151 

196 

0.77 

21 

TABLE    13. — Illustr.\tion    of   Fall   in    Respiratory    Quotient   of   Mild   Diabetic  * 
Case  714.     Female.     Aged  38  years,  9  months.     Weight  53  kilos. 


R.   Q. 

Urine 
Sugar 

Dietf 

Date 

Carb. 

Prot. 

Fat 

Alcohol 

gm. 

gm. 

gm. 

gm. 

Dec.    3 

4.4% 

+  + 

+  + 

+  + 

0 

Dec.     4-  5 

20   gm.  t 

+ 

+ 

+ 

10 

Dec.      5-  6 

6.78 

0 

0 

0 

0 

25 

Dec.      6-  7 

0.75 

0 

15 

40 

45 

10 

Dec.      7-  8 

0.75 

0 

15 

45 

60 

7 

Dec.    10-11 

0.73 

0 

15 

55 

100 

9 

*  Tests  were  made  fasting  at  8  a.    m.,  which   was   one   hour  after  the  collection   of   the 
twenty-four-hour  urine, 
t  Approximate. 
I  In  fourteen  hours. 

have  other  observers.  It  is  well  exemplified  by  the  change  in  the 
respiratory  quotient  in  Case  714.  This  patient,  with  only  moderate 
acidosis,  became  sugar-free  on  April  16,  1914,  following  fourteen 
days  of  treatment.  On  Dec.  3,  1914,  she  reentered  the  hospital  with 
4.4  per  cent,  of  sugar,  but  under  fasting  treatment  became  sugar-free 
after  the  omission  of  four  meals.  The  respiratory  quotient  on  suc- 
cessive days  is  shown  in  Table  13. 

It  will  be  seen  that  whereas  the  respiratory  quotient  was  0.78  on 
entrance,  owing  undoubtedly  to  the  oxidation  of  some  of  the  carbo- 


23 

hydrate  ingested,  though  much  at  the  same  time  was  being  lost  in 
the  urine,  this  rapidly  decreased  to  0.73  under  starvation  followed  by 
a  low  carbohydrate  diet.  Yet  this  could  not  be  considered  a  severe 
case  of  diabetes.  The  quotient  was  low  simply  because  the  woman 
was  living  almost  exclusively  on  a  fat  protein  diet. 

The  problem  of  drawing  inferences  from  the  respiratory  quotient 
in  diabetes  is  complicated  by  the  fact  that  much  of  even  the  little  car- 
bohydrate which  is  given  to  a  diabetic  patient  is  lost  in  the  urine.  The 
patient  really  approaches  the  condition  of  the  fasting  man  in  that  he 
is  living  exclusively  on  fat  and  protein,  although  in  this  case  not  that 
of  his  own  body.  If  all  the  carbohydrate  ingested  is  lost  in  the  urine, 
his  respiratory  quotient  Avould  be  0.72.  But  there  are  other  complica- 
tions. Occasionally  cases  of  diabetes  are  seen  in  which  the  sugar  in 
the  urine  exceeds  that  of  the  diet,  and  speculation  at  once  arises  as  to 
the  source  of  this  excess  of  sugar.  Magnus-Levy-"  has  pointed  out 
that  if  the  sugar  in  the  urine  amounted  to  60  gm.  and  the  protein  in 
the  diet  to  100  gm.,  the  additional  quantity  of  oxygen  which  would 
be  demanded  to  form  this  amount  of  sugar  out  of  protein  would  lower 
the  respiratory  quotient  to  0.70.  The  situation  is  still  further  compli- 
cated by  the  presence  of  unoxidized  acid  bodies  in  the  urine,  amount- 
ing frequently  to  20  to  40  gm.  and  occasionally  to  60  gm.  calculated 
as  beta-oxybutyric  acid.  The  amount  of  oxygen  consumed  in  the 
formation  of  these  bodies — for  beta-oxybutyric  acid  is  far  richer  in 
oxygen  than  are  protein  and  fat — would  again  lower  the  quotient,  and 
it  has  been  calculated  by  Magnus-Levy  that  the  respiratory  quotient 
of  a  diabetic  patient  presenting  60  gm.  of  sugar  in  the  urine  for  100 
gm.  of  protein  in  the  diet,  and  excreting  20  gm.  of  beta-oxybutyric 
acid,  would  fall  as  low  as  0.69.  For  convenience,  these  figures  are 
summarized.  The  respiratory  quotient  of  the  fasting  man  at  the 
Nutrition  Laboratory  was  0.72.  The  calculated  respiratory  quotient 
of  a  normal  individual  who  is  burning  15  per  cent,  protein  and  S5  per 
cent,  fat  is  0.72.  The  theoretical  respiratory  quotient  of  a  diabetic 
individual  excreting  all  the  carbohydrate  in  the  diet,  and  60  gm.  of 
glucose  for  each  100  gm.  of  protein  in  the  diet,  is  0.70.  The  theo- 
retical respiratory  quotient  of  the  diabetic  individual  excreting  60  gm. 
glucose  for  100  gm.  protein  and  20  gm.  beta-oxybutyric  acid  as  well, 
is  0.69.  These  calculations  presuppose  that  the  sugar  and  beta-oxy- 
butyric acid  excreted  Avere  formed  during  the  same  twenty-four  hours, 
but  who  knows  whether  this  is  the  case?  The  theoretical  nonprotein 
respiratory  quotient  of  a  case  of  diabetes  living  on  fat  and  the  non- 
carbohydrate  part  of  the  protein  molecule,  as  calculated  by  Lusk,  is 
also  0.69. 

Table  14  shows  the  theoretical  respiratory  quotient,  which  should 
be  reached  under  varying  conditions  of  diet  for  a  normal  individual. 


24 

and  the  changes  which  theoretically  are  present  under  special  condi- 
tions in  diabetes.  Figures  of  this  type  have  dominated  the  discussions 
of  the  metabolism  in  diabetes  from  the  start,  and  whenever  experi- 
ments have  not  produced  figures  comparable  with  these,  they  have 
often  been  considered  erroneous.  We  are  taught  to  believe  thai  cases 
of  diabetes  are  not  severe  unless  the  respiratory  quotient  is  0.69.  It 
is  questionable,  however,  whether  the  experimental  data  at  our  disposal 
enable  us  to  say  that  our  theories  are  backed  up  by  the  results  which 
we  obtain.  If  one  looks  over  the  lists  of  respiratory  quotients  obtained 
in  successive  periods  with  any  variety  of  respiratory  apparatus  or 
calorimeter,  he  will  be  shocked  at  the  discrepancy  and  forced  to  the 
belief  that  any  argument  based  on  a  change  in  the  respiratory  quotient 
of  one  point  is  unjustifiable,  and  that  any  argument  which  is  based  on  a 
change  in  the  respiratory  quotient  of  two  points  really  hangs  on  a 


TABLE    14. — Theoretical   Respiratory 

Quotients 

(from  Magnus-Levy) 

Diet 

Calories 

R.  Q. 

Protein,     100  gm.    (100  X  4.1  =  410  ) 
Carb..        567  gm.    (567  X  4.1  =  2325) 

2,735 

0.97 

Protein,    100  gm.   (100  X  4.1  =  410  ) 
Fat,           250  gm.   (250  X  9.3  =  2325) 

2,735 

0.72 

Loss  in   Urine 
Sugar,  60   gm.    (60  X  4.1  =  246) 

2,489 

0.70 

Loss  in   Urine 

Sugar,              60   gm.    (60  X  4.1  =  246) 
B-Oxy.  acid,  20  gm.   (20  X  4.7  =    94) 

2,395 

0.69 

Total   loss  =  340 

very  slender  thread.  A  change  of  three  points  is,  however,  deserving 
of  consideration,  but  modesty  should  rule'  in  conclusions  which  are  to 
be  drawn  from  any  given  set  of  experiments. 

It  is  appropriate  to  discuss  here  what  constitutes  a  severe  diabetes. 
At  the  outset  it  can  be  said  for  our  own  encouragement  that  Naunyn 
did  not  pretend  to  be  able  to  distinguish  accurately  between  the  various 
types.  Usually  by  severe  diabetes  is  understood  those  cases  in  which 
— to  quote  von  Noorden — "notwithsanding  a  prolonged,  extreme  car- 
bohydrate-free diet,  the  urine  contains  sugar."  By  an  extreme  car- 
bohydrate-free diet  von  Noorden  undoubtedly  meant  one  containing 
protein,  fat  and  a  few  green  vegetables — in  other  words,  a  diet  with 
10  gm.  carbohydrate,  more  or  less — ^hot  a  strictly  fat-protein  diet. 
The  definition  is  also  open  to  objection,  because  one  frequently  meets 
with  cases  of  diabetes  of  long  duration  in  which  but  a  small  per  cent, 
of  the  carbohydrate  intake  is  excreted  in  the  urine,  yet  this  persists 
for  many  days  on  an  extreme  carbohydrate-free  diet,  but  the  case 
could  not  be  classed  as  severe. 


25 

Another  method  of  classification  is  adopted  by  Lusk,  who  con- 
siders cases  severe  in  which,  when  the  patients  are  put  on  a  protein- 
fat  diet,  there  is  a  dextrose-nitrogen  ratio  of  3.65  :1.  By  this  he  means 
that  3.65  gm.  of  dextrose  appear  in  the  urine  for  1  gm.  of  nitrogen,  or 
the  6  gm.  of  protein  which  it  represents.  In  other  words,  60  per  cent, 
(actually  3.65^-6.25=58.4  per  cent.)  of  the  protein  burned  by  the  body 
appears  in  the  urine  in  the  form  of  sugar.  Lusk  considers  that  this 
is  the  greatest  possible  amount  of  sugar  which  can  appear  in  the  urine 
oa  a  carbohydrate-free  diet,  and  he  assumes  that  it  comes  wholly  from 
protein.  This  conclusion  has  been  reached  with  many  observations 
on  dogs,  following  injections  of  phloridzin,  and  by  one  case  of  diabetes 
coming  under  his  personal  observation,  and  he  refers  to  other  cases 
selected  from  the  literature. 

Unfortunately,  or  perhaps  fortunately,  neither  of  these  methods 
of  classification  at  the  present  time  are  wholly  satisfactory,  because, 
thanks  to  Dr.  Allen,  our  patients  now  become  sugar-free  very  readily. 
It  is  possible  that  fasting  will  not  remove  the  sugar  from  the  urine  of 
all  diabetic  patients,  but  this  has  been  my  experience  with  every  case 
when  I  have  followed  Dr.  Allen's  directions,  and  my  experience 
coincides  with  that  of  many  others.  It  may  be  that  recent  cases  of 
diabetes  have  been  of  a  different  type  from  those  hitherto  encountered, 
but  this  is  hardly  possible.  Consequently  we  cannot  adopt  the  defini- 
tion of  von  Noorden,  and  it  is  embarrasing  to  adopt  the  precise  defini- 
tion of  Lusk.  The  dextrose-nitrogen  ratio  vanishes  with  fasting,  and 
the  clinician  does  not  wish  to  expose  his  patient  before  beginning 
fasting  to  the  dangers  of  a  protein- fat  diet  simply  to  determine  the 
severity  of  his  case.  I  am  hoping  that  with  the  added  knowledge  of 
diabetes  which  the  introduction  of  fasting  has  brought  about,  Professor 
Lusk  wall  pursue  his  studies  further  and  give  us  definite  rules  for  test- 
ing the  severity  of  the  disease.  Perhaps  definite  quantities  of  protein 
alone  or  some  special  form  of  protein  or  derivative  of  protein  could 
be  administered  to  these  patients,  and  the  amount  of  sugar  in  the  urine 
determined.  Should  this  method  not  furnish  satisfactory  results, 
another  series  could  be  carried  out  in  which  varying  quantities  of  fat 
as  well  as  protein  could  be  added,  and  if  a  third  factor  were  necessary, 
the  calories  per  kilo  could  be  standardized.  But  we  can  trust  Profes- 
sor Lusk  to  give  us  help.  Of  course  dextrose-nitrogen  ratios  are  of 
little  significance  without  simultaneous  reports  of  the  blood  sugar. 

In  the  data  which  will  follow,  consideration  will  be  taken  of  both 
von  Noorden's  and  Lusk's  classification,  but  also  the  severity  of  the 
cases  will  be  indicated  by  a  statement  of  the  time  intervening  between 
the  period  of  observation  and  death  in  coma.  It  w^ould  seem  as  if  the 
severity  of  the  type  of  diabetes  which  resulted  in  death  by  coma  should 
challenge  criticism. 


26 

As  the  periods  of  observation  before  death  in  coma  are  of  impor- 
tance, the  intervals  between  the  determination  of  the  respiratory 
quotient  of  the  patient  and  death  are  given.  See  Table  16,  which  will 
later  be  discussed  more  in  detail.  This  appears  far  more  rational  than 
to  give  the  duration  of  the  course  of  the  disease,  for  many  patients 
present  a  mild  type  of  diabetes  for  many  "years,  changing  over  to  a 
severe  type  at  a  comparatively  short  period  before  death. 

Table  15  summarizes  the  respiratory  quotients  of  cases  of  diabetes 
considered  severe  by  their  observers : 

TABLE    15. — Respiratory    Quotient    in    Severe    Diabetes 


Year 

Observers 

Cases 

R.  Q. 

1894 

1897 

1905 

1907 
1908-1911 

1912 

1912 
191'-1914 

Weintraud  and  Laves:  Ztschr.  f.  physiol.  Chem., 

1894,  xix,   603. 
Nehring-Schmoll:    Ztschr.    f.    klin.    Med.,    1897, 

xiii,    59. 
Magnus-Levy:    Ztschr.    f.    klin.    Med.,    1905,   Ivi, 

86. 
Mohr:  Ztschr.  f.  exper.  Path.  u.  Therap.,  1907. 

iv,   910. 
Benedict   and    Joslin:    Carnegie    Inst,    of   Wash- 
ington, Publications   136  and   176,  1910,   1912. 
Roily:    Deutsch.   Arch.    f.    klin.    Med.,    1912,   cv, 

494. 
Grafe  and  Wolf:  Deutsch.  Arch.  f.   klin.  Med., 

1912,   cvii,   201. 
Benedict  and  Joslin,   1914-15 

1 
2 
2 
1 
19 
8 
3 
7 

0.70 
0.72 
0.71 
0.72 
0.73 
0.74 
0.74 
0  73 

Total    43 

Average  0.73 

It  will  be  seen  that  there  is  surprising  unanimity  of  agreement 
among  the  different  groups.  It  should  be  stated  that  Leimdorfer^''  has 
obtained  much  lower  quotients  varying  between  0.64  and  0.68  with 
five  cases  which  he  considered  severe.  His  figures,  however,  have  not 
been  generally  accepted.  One  of  the  cases  which  he  considered  mild 
at  no  time  showed  a  respiratory  quotient  above  0.70.  According  to 
the  computations  given  above  from  Magnus-Levy,  it  was  shown  that, 
theoretically,  in  a  diabetic  patient  with  60  gm.  of  sugar  in  the  urine 
for  each  100  gm.  of  protein  in  the  diet — in  other  words,  approximately 
the  Lusk  dextrose-nitrogen  ratio — and  with  20  gm.  of  beta-oxybutyric 
acid,  the  respiratory  quotient  would  not  go  below  0.69,  and  he  further 
points  out  that,  in  order  for  the  ratio  to  sink  to  0.653,  150  gm.  of 
sugar  must  be  formed  from  150  gm.  of  protein,  and  40  gm.  of  beta-' 
oxybutyric  acid  must  appear  in  the  urine  when  the  patient  is  on  a 
diet  of  150  gm.  protein  and  250  gm.  fat.  A  respiratory  quotient  of 
0.653  is  a  figure  so  low  that  it  should  be  entertained  with  scepticism. 
The  average  respiratory  quotient  of  0.73  for  forty-three  cases  df 
diabetes  clinically  considered  severe  is  a  far  safer  figure  to  follow  than 


29.  Leimdorfer:    Bio-Chem.  Ztschr.,  1912,  xl,  326. 


27 

to  pick  out  one,  two  or  three  from  the  forty-three  cases  and  say  that 
these  represent  severe  cases  of  diabetes  and  the  others  do  not.  The 
errors  of  the  determinations  of  the  quotients  are  so  great  that  the 
average  figures  are  safer  than  the  individual  ones.  These  respiratory 
quotients,  as  Grafe  and  Wolf^°  pointed  out,  show  that  at  least  some 
carbohydrates  were  being  oxidized  by  severe  diabetic  patients.  They 
also  pointed  out  that  with  the  improvement  of  patients  the  respiratory 
quotients  increased  from  0.743  to  0.817  in  a  fasting  condition. 

These  figures  suggest  at  the  first  glance  that  very  little  carbo- 
hydrate was  burned  in  this  group  of  severe  cases  of  diabetes.  The 
respiratory  quotients  are  identical  with  the  quotients  obtained  under 
similar  conditions  with  the  fasting  man  at  the  Nutrition  Laboratory, 
though  his  average  for  the  whole  day  for  the  fasting  period  was  0.72. 
But  we  must  remember  that  two  corrections  are  to  be  made  in  these 
figures ;  first,  sugar  has  been  lost  in  the  urine  which  has  been  formed 
from  protein,  and  second,  there  have  been  varying  amounts  of  beta- 
oxybutyric  acid,  diacetic  acid  and  acetone  excreted.  Both  of  these 
processes  represent  processes  of  oxidation  and  by  demanding  addi- 
tional oxygen  for  which  no  carbon  dioxid  is  produced  tend  to  lower 
the  respiratory  quotient.  Therefore,  if  we  grant  that  the  series  repre- 
sents cases  of  severe  diabetes,  we  must  reach  the  conclusion  that  these 
diabetic  patients  utilized  some  carbohydrate,  and  that  their  respiratory 
quotients  would  have  been  several  points  above  0.73,  had  they  not  been 
lowered  to  0.73  by  the  production  of  sugar  from  protein  and  the 
formation  of  acid  bodies. 

Are  the  cases  reported  in  Table  15  severe?  At  least  no  cases  of 
greater  severity  have  been  hitherto  published.  By  von  Noorden's  cri- 
terion they  might  be  considered  severe,  for  they  did  not  become  sugar- 
free  with  restricted  diet,  yet  it  is  true  that  this  restricted  diet  was  not 
so  rigid  as  is  often  employed  on  account  of  the  marked  acidosis.  If 
we  accept  Lusk's  criterion  (and  I  am  not  ready  to  do  so  until  a  second 
human  case  is  studied  under  modern  conditions")  they  were  not 
severe.  Not  one  of  Benedict's  and  my  cases  showed  a  persistent 
D:N  ratio  of  3.65:1.  Yet  the  clinical  facts  point  to  severity.  In 
the  first  group  of  nineteen  cases  of  diabetes  reported  in  1908-1912  by 
Benedict  and  myself,  eighteen  patients  are  dead  and  of  these  fifteen 


30.  Grafe  and  Wolf:    Deutsch.  Arch.  f.  klin.  Med.,  1912,  cvii,  201. 

31.  By  modern  conditions  I  mean  (1)  exclusive  fat-protein  diet,  (2)  under 
surroundings  which  make  errors  in  diet  impossible,  (3)  a  duration  of  at  least 
seven  days  to  exclude  the  washing  out  of  stored  carbohydrate,  (4)  a  constant 
(not  falling)  D :  N  ratio  of  3.65 :  1  for  the  last  three  of  the  seven  days,  and 
(5)  several  daily  blood  sugar  determinations  to  furnish  some  proof,  inade- 
quate though  it  be,  that  the  sugar  in  the  urine  has  not  come  from  that  left  over 
in  the  blood.  At  present  I  cannot  advocate  such  a  test  because  of  the  danger 
of  acidosis,  and  believe  it  better  to  leave  the  question  "in  this  form,  undecided. 


28 

died  in  coma.  This  fact  can  be  taken  as  a  measure  of  their  severity. 
I  do  not  believe,  however,  that  this  alone  justified  us  in  saying  that  a 
case  of  diabetes  is  of  the  severest  type.  I  conceive  it  possible,  for  a 
moderately  severe  case  of  diabetes,  by  sudden  changes  of  diet,  to  be 
driven  into  coma  accidentally.  This  was  done  years  ago,  when  tiiabetic 
patients  who  were  living  on  a  free  diet  on  coming  to  the  hospital  were 
suddenly  deprived  of  carbohydrate  and  the  fat  and  protein  were 
increased.  It  appears  to  me  quite  probable  that  most  cases  of  coma  in 
diabetes  have  occurred  long  before  the  disease  had  reached  its  greatest 
severity,  and  I  wish  to  point  out  that  therein  lies  great  hope  for  the 
future. 

It  will  be  of  interest,  however,  to  note  the  respiratory  quotient  of 
a  group  of  six  cases  of  diabetes  all  ending  in  coma,  death  occurring 
within  a  period  of  44  to  14  days  from  the  time  of  observation,  and 
to  compare  these  with  a  group  of  patients  whose  respiratory  quotient 
was  observed  at  a  greater  interval  from  death  by  coma.  This  is 
shown  by  Table  16. 


TABLE    16. — Respiratory    Quotient    in    Severe    Diabetes  :    Comparison    of 
Fatal    Cases   and   Cases   of   Living    Patients 


Fatal  Cases 

Living  Patients 

No.    of 
Cases 

Days  Before 

Coma 

R.   Q. 

Case   No. 

Days  Before* 
March  1,  '15 

R.  Q. 

6 
8 

44-14 
442-70 

0.71 
0.74 

SS2 
765 
786 
806 
4   Cases 

801 
125 
111 

72 
801-72 

0.72 
0.73 
0.71 
0.70 
0.715 

*  All  of  these  patients  were  in  good  condition  May  1,  1915,  which  would  add  sixty-two 
days  to  the  duration  since  the  observations  were  made. 

A  consideration  of  this  table  suggests  that  with  approaching  death 
the  respiratory  quotient  falls.  It  will  be  seen  that  the  cases  ending 
fatally  v/ithin  a  period  of  from  44  to  14  days  from  the  time  of  observa- 
tion, gave  a  quotient  of  0.71,  as  contrasted  with  a  quotient  of  0.74  in 
cases  terminating  fatally  in  coma  at  an  interval  from  death  of  from 
442  to  70  days.  If  we  had  these  figures  alone,  the  inference  might  be 
justified,  but  caution  is  necessary  before  drawing  such  a-  conclusion. 
Four  living  diabetic  patients  show  a  respiratory  quotient  almost  as 
low — 0.715.  Instead  of  progression  toward  death  by  coma,  their 
general  condition  has  improved.  In  other  words,  a  falling  respiratory 
quotient  does  not  necessarily  mean  approaching  death  by  coma.  It 
does  mean  that  these  patients  have  lived  for  prolonged  periods  on  an 
almost  exclusively  fat-protein  diet  and  suggests  that  they  are  form- 
ing carbohydrate  out  of  protein  and  producing  acid  bodies. 


29 

Tt  should  be  said  that  all  of  these  living  patients  have  been  treated 
either  by  much  restricted  diets  or  by  fasting  as  advocated  by  Dr.  Allen. 
When  they  were  first  seen  the  cases  appeared  to  be  quite  as  severe 
as  those  earlier  studied  which  ended  fatally  in  coma.  What  shall  we 
say  of  them  at  present?  None  of  these  patients  can  be  considered 
well,  but  all  lead  a  comfortable  life  at  home. 

The  group  of  patients  dying  within  a  period  of  from  forty-four 
to  fourteen  days  deserves  further  comment.  The  average  quotient  of 
these  cases  was  0.71.  From  four  of  these  the  non-protein  respiratory 
quotient  has  been  reckoned,  and  it  amounted  to  0.695.  This  respira- 
tory quotient  implies  that  much  material  must  have  been  formed  in 
the  course  of  the  metabolism  which  used  a  portion  of  the  oxygen. 
This  was  especially  true  of  Case  246,  in  which  there  was  a  respiratory 
quotient  of  0.69,  which  was  based  on  an  average  of  twenty-nine 
periods,  most  of  which  were  fasting.^-  Stimulated  by  inquiries  from 
Professor  Lusk,  I  am  fortunately  able  to  show  the  cause  of  the  par- 
ticularly low  quotient  in  this  patient.  His  diet  and  urinary  analyses 
will  be  found  in  Tables  17  and  18.  The  average  daily  urinary  nitrogen 
for  the  six  days  of  observation  was  16.6  gm.,  and  it  was  considered  that 
this  represented  approximately  the  metabolism  of  100  gm.  protein. 
The  beta-oxybutyric  acid  was  46.6  gm.  daily  and  allowing  for  acetone 
and  diacetic  acid  the  total  excretion  of  acid  bodies  was  assumed  to  be 
60  gm.  The  fat  in  the  diet  as  originally  recorded  was  probably  inac- 
curate, and  I  believe  165  gm.  daily  near  to  the  exact  quantity.  From 
these  tables  it  will  be  seen  that  the  daily  carbohydrate  in  the  diet  was 
71  gm.,  and  the  dextrose  excreted  was  102  gm.  giving  a  minus  balance 
of  31  gm.  This,  with  the  16.6  gm.  nitrogen  in  the  urine,  gives  a  D:  N 
ration  of  only  1.9  to  1.  In  Table  18  are  placed  the  data  from  which 
the  respiratory  quotient  can  be  calculated  from  the  diet  and  urine, 
and  they  show  that  after  deductions  for  dextrose  and  acetone  bodies, 
the  theoretical  quotient  would  be  0.692,  which  it  will  be  remembered 
was  identical  with  the  respiratory  quotient  found  by  experiment. 
These  tables  are  submitted  as  proof  that  a  quotient  of  0.69  does  not 
necessarily  mean  that  the  capacity  for  burning  carbohydrate  has  been 
totally  abolished. 

Computations  of  a  similar  character  by  Grafe  and  Wolf^°  lead  to 
the  same  conclusion. 

According  to  these  writers,  "the  conception  which  on  the  whole 
appears  to  have  the  greatest  probability  is  that  even  the  severest  dia- 
betic has  at  his  disposal  20  to  30  gm.  of  glycogen  for  combustion  or 
synthesis,  thirteen  to  twenty  hours  after  a  meal  containing  a  minimal 


32.  Benedict  and  Joslin :    Metabolism  in  Diabetes,   Pub.   Carnegie   Institution 
of  Washington,  1910,  No.  136,  p.  68. 


30 

amount  of  carbohydrate.  Perhaps  the  complete  loss  of  the  power  of 
combustion  of  sugar  is,  broadly  speaking,  no  longer  consistent 
with  life." 

TABLE   17. — Metabolism   in  a   Case  of   Severe  Diabetes  with   a  *Respira- 
TORY   Quotient   of   0.69  * 

Case  C,  No.  246.    Male.    Acute  onset  at  28.    Death  in  coma  in  fifteen  months. 


Urine 

Diet 

Sodium 

Bicarb. 

Gm. 

Day 

Volume, 
e.c. 

N, 
Gm. 

NHs 

Gm. 

B-oxy., 
Gm. 

Dex- 
trose, 
Gm. 

Garb., 
Gm. 

Prot., 
Gm. 

Fat, 
Gm. 

Alco- 
hol, 
Gm. 

1 

2.g.S5 

16.3 

4.8 

29 

72 

15 

13 

55 

15 

0 

2 

3,710 

13.3 

6.0 

34 

106 

98 

22 

225 

30 

0 

8 

4,370 

19.6 

5.5 

61 

134 

65 

100 

200 

30 

60 

4 

4,035 

19.4 

5.4 

61 

107 

65 

100 

200 

30 

60 

5 

3,330 

14.7 

5.6 

46 

100 

125 

45 

100 

30 

25 

6 

3,765 

16.3 

5.0 

48 

93 

65 

100 

200 

22 

25 

Ave. 

3,691 

16.6 

5.2 

j      46.6 

102 

71 

65 

165 

26 

28 

*DaiIy  protein  metabolism  estimated  at  100  gm.     Total  acetone  bodies  estimated  at  60  gm. 

Carbohydrate  in  diet,  71  gm. 

Dextrose  in  urine,  102  gm. 

Carbohydrate  balance,  31  gm.  .  ij 

D  :  N  ratio,  1.9  :  1.0. 

TABLE   18.— To   Supplement   Table   17* 
Case  C,  No.  246. 


Diet                                           Gm. 

Calories 

,.02 

Liters 

CO3 

Liters 

R.  Q. 

Protein      100   X   4.1 

Fat    165   X   9.3 

Carbohydrate    71   X   4.1 

=:     410 

-  1535 
=     291 

—  182 

96.6 

333.1 

58.9 

37.9 

78.2 

235.5 

58.9 

25.3 

Alcohol  26  X       7 

Lost  in  Urine 

Dextrose    102   X   3.7 

Acetone  bodies  as  B-oxyb..'60  X   4.5 

2418 

=     337 

r:     243 

620 

526.5 

76.1 

58.1 

134.2 

397.9 

76.1 

51.6 

127.7 

0.756 

.1798 

392.3 

270.2 

0.692 

*  The  respiratory  quotient  found,  based  on  an  average  of  29  periods,  chiefly  fasting 
was  0.69. 

Effect  of  Food  on  Utilisation  of  Carbohydrates  in  Severe  Diabetes. 
— A  moderate  number  of  experiments  on  the  effect  of  food  on  severe 
diabetics  has  been  recorded,  but  the  actual  number  of  experiments  to 
determine  the  effect  of  carbohydrate  on  the  respiratory  metabolism  is 
very  limited.     Such  experiments  have  been  published  by  Leo,^"  who 


33.  Leo:  Ztschr.  f.  Klin.  Med.,  1891,  xix,  101. 


31 

considered  that  the  respiratory  quotient  did  increase  in  two  cases  of 
severe  diabetes,  although  this  was  not  uniformly  the  rule  and  he  con- 
cludes that  even  in  severe  diabetes  a  part  of  the  sugar  ingested  or 
formed  in  the  body  is  utilized. 

Nehring  and  Schmoll"^'  tested  the  effect  of  carbohydrates  also  in 
two  severe  cases  of  diabetes,  but  were  unable  in  either  to  show  an 
increase  in  the  respiratory  quotient.  Frequently  a  fall  instead  of  a 
rise  in  the  quotient  took  place.  Benedict  and  Joslin,-'^  in  a  series  of 
experiments  chiefly  with  bread  and  dextrose,  state  that  "the  ingestion 
of  carbohydrate  produced  no  very  material  alteration  in  the  metab- 
olism as  a  whole,"  and  later  "no  evidence  can  be  found  of  a  com- 
bustion of  carbohydrate  .  .  ."  Two  years  later  a  series  of  experi- 
ments with  oatmeal  and  levulose  were  reported,  but  without  com- 
ment.^^ 

Rolly,^^  in  a  series  of  experiments,  tested  the  comparative  efifects  of 
oats,  rye,  wheat,  lentils  and  green  cornmeal  on  diabetic  patients.  Unfor- 
tunately, few  of  the  experiments  were  preceded  by  control  periods. 
Two  of  his  cases  he  considers  severe.  In  Case  1,  at  three,  five  and  six 
hours  after  70  gm.  of  oatmeal  were  administered,  the  respiratory  quo- 
tient was  0.73.  After  70  gm.  of  Avheat  meal  it  was  0.76.  The  respira- 
tory quotient  of  his  Case  V  after  80  gm.  of  oatmeal  was  0.71,  after 
80  gm.  of  rye  meal  was  0.73,  and  after  80  gm.  of  wheat  meal  was  0.71. 
Two  of  his  other  cases  were  only  moderately  severe,  and  the  other 
only  a  light  case,  and  all  showed  an  increase  in  the  respiratory  quotient 
after  their  meals  reaching  up  to  0.83,  0.85  and  0.84  respectively.  It 
will  be  noted,  furthermore,  that  of  the  two  severe  cases,  in  the  first 
the  quotient  following  administration  of  wheat  meal  which  was  given 
after  oatmeal  reached  0.76. 

Roth^^  records  slight  increase  of  the  respiratory  quotient  following 
the  administration  of  carbohydrate.  The  experiments,  however,  lose 
much  of  their  value  because  of  the  absence  of  fasting  controls  on  the 
day  the  carbohydrates  were  given. 

Falta^^  has  mentioned  several  experiments  designed  to  show  the 
effect  of  the  oatmeal  cure  on  the  respiratory  quotient.  The  data  of 
the  experiments  are  not  given,  but  he  states  that  with  one  moderately 
severe  diabetic  the  respiratory  quotient  rose  only  on  the  third  day  of 
an  oatmeal  cure,  in  which  400  gm.  had  been  given  daily.    Despite  this 


34.  Nehring  and  Schmoll :    Ztschr.  f.  klin.  Med.,  1897,  xxxi,  59. 

35.  Benedict  and  Joslin :    Loc.  cit.  (Note  32)  p.  215. 

36.  Schilling:  Inaug.  Dissert.,  Leipzig,  1911,  tested  the  effects  of  various 
meals  on  the  respiratory  quotient  of  one  severe,  one  mild  and  two  moderately 
severe  cases  of  diabetes,  and  demonstrated  no  specificity  for  oatmeal.  With  the 
severe  case  the  results  were  inconstant,  but  usually  tended  to  show  a  slight 
increase  in  the  respiratory  quotient. 

37.  Roily:  Deutsch.  Arch.  f.  klin.  Med.,  1912,  cv,  494. 

38.  Roth:  Wien.  klin.  Wchnschr.,  1912,  xlvii,  1864.' 


32 

enormous  quantity  of  oatmeal,  no  glycosuria  was  observed.  It  is 
unfortunate  that  I  have  not  been  able  to  find  a  later  publication  which 
was  promised.  He  furthermore  makes  the  interesting  statement, 
which  is  so  remarkable  as  to  invite  confirmation,  that  a  similar  result 
was  encountered  with  a  normal  individual,  whose  carbohydrate  depots 
had  been  robbed  by  living  on  a  diet  poor- in  carbohydrates  for  a  long 
time.  It  would  appear  that  only  after  these  depleted  carbohydrate 
stores  were  replenished,  did  the  normal  individual,  like  the  diabetic, 
begin  to  burn  carbohydrate.  His  results  are  in  striking  contrast  to  the 
changes  in  respiratory  quotient  which  were  shown  by  the  fasting  man 
at  the  Nutrition  Laboratory.  At  the  end  of  his  fast  of  thirty-one 
days  he  ate  food  almost  exclusively  in  the  form  of  carbohydrate  and 
the  quotient  promptly  rose  to  0.79  and  0.96  on  the  second  and  third 
days  respectively,  emphasizing  the  fact  that  in  a  mixed  diet  carbohy- 
drates are  burned  much  earlier.  He  further  states  that  on  a  meat  diet 
or  on  a  diet  with  a  moderate  amount  of  carbohydrate  the  diabetic 
patient  seldom  shows  a  quotient  above  0.74,  and  he  also  noted  the  fact, 
to  which  attention  has  been  called  by  Nehring  and  Schmoll,  and  which 
is  also  borne  out  by  our  own  series  of  cases,  that  following  the  adminis- 
tration of  carbohydrate  a  considerable  quantity  of  carbohydrate  not 
only  remains  in  the  body,  but  the  respiratory  quotient  remains  low. 
Intravenous  injections  of  sugar  (30  gm.)  given  by  Falta  to  severe  dia- 
betics, who  had  eaten  300  gm.  of  oatmeal  for  three  days  without  gly- 
cosuria, brought  about  an  evident  glycosuria,  but  the  respiratory  quo- 
tient rose  proportionately  little.  In  the  case  of  a  severe  diabetic  there 
was  no  increase,  but  a  still  further  lowering  of  the  already  low  respira- 
tory quotient. 

The  present  series  of  experiments  with  foods  which  I  have  to 
report  represent  a  part  of  the  experiments  on  diabetics  whose  metab- 
olism following  the  administration  of  food  was  studied  at  the  Nutrition 
Laboratory  since  1910. 

Three  experiments  have  been  conducted  with  levulose.  In  Case  332 
100  gm.  of  levulose  were  administered  when  the  patient  was  fasting. 
This  patient  was  a  severe  diabetic,  weight  40  kg.,  in  the  twenty-fourth 
month  of  her  illness,  and  died  five  months  later.  The  respiratory 
quotient  before  the  levulose  was  administered  was  0.72,  and  following 
the  levulose  the  quotient  was  determined  in  six  different  periods  during 
the  following  three  hours  and  showed  an  average  of  0.69.  Despite 
the  fall  in  the  respiratory  quotient,  the  total  metabolism  increased 
markedly,  although  apparently  most  of  the  levulose  was  excreted  in 
the  urine.  Unfortunately,  it  is  impossible  to  state  how  much  of  the 
120  gm.  of  sugar  in  the  urine  for  this  twenty-four  hours  came  from 
the  levulose  and  how  much  from  carbohydrates  of  the  preceding  day. 


33 


Our  records  indicate  that  the  patient  was  on  a  diet  containing  approxi- 
mately 100  gm.  of  carbohydrate.  This  fact  is  of  interest  in  compari- 
son with  the  next  two  cases,  in  which  also  levulose  was  given. 

TABLE    19. — Effect   of   Levulose   on   a    Severe   Diabetic 
Case  332.     Female.    Aged  27  years.    Weight  40  kilos. 


Date 

Condition 

CO. 

Per   Min. 

O. 
Per   Min. 

R.  Q. 

Calories  per 
Kilo,    per 
24   Hours 

3/31/11 

Fasting 

c.c. 

c.c. 

10:50 
11:23 

Fasting 
Fasting 

151 

145 

205 
211 

0.74 
0.69 

35 
36 

100  gm.   levulose 


12:16 

172 

271 

0.63 

46 

12:44 

184 

261 

0.70 

44 

1:30 

180 

246 

0.73 

42 

2:05 

172 

235 

0.73 

40 

2:28 

171 

250 

0.68 

42 

2:53 

166 

240 

0.69 

40 

4/2/11 

8:17 

Fasting 

148 

199 

0.75 

34 

8:45 

Fasting 

151 

203 

0.74 

35 

9:14 

Fasting 

154 

213 

0.72 

36 

Oatmeal  =  70  ±  gm.  carb.,  38  gm.  butter 


10:13 

163 

234 

0.70 

39 

10:39 

167 

228 

0.73 

39 

11:08 

177 

238 

0.75 

40 

12:12 

170 

230 

0.74 

39 

1:28 

154 

206 

0.75 

35 

2:37 

163 

209 

0.78 

36 

TABLE    20. — Effect    of    Levulose    on    Respiratory    Quotient    of    Diabetic 

Patients 


Case 

Dura- 
tion, 
Months 

Month 

Ob- 
served 

Carbo- 
hyd. 

Preceding 
Day, 
Gm.  ' 

Levu- 
lose, Gm. 

'      Sugar 

in 

Urine 

24  Hours, 

Gm. 

R.Q. 

Before           After 

332 
652 
785 

Dead 

28 
Alive 

32 

23 

23 
18 
20 

100± 
30 
20 

100 

100 
81» 

120 
3 
7 

0.72                0.69 
0.72                0.76 
No  increase 

*81  gm.  levulose  and  later 
9  gm.  carb.  as  vegetables 

90  gm.  total. 

In  Case  552  also  100  gm.  of  levulose  was  administered,  but  this 
was  given  after  a  prolonged  period  of  low  carbohydrate  feeding.  On 
the  day  previous  to  the  experiment  the  carbohydrates  in  the  diet 
amounted  to  30  gm.  The  quantity  of  sugar  in  the  urine  in  this  case 
during  the  twenty-four  hours   of  the  experiment  was   3  gm.     The 


34 

respiratory  quotient  rose  4  points,  namely,  from  0.72  to  0.76  after  the 
levulose. 

The  third  case,  No.  785  (Table  20),  was  that  of  a  boy,  aged  16, 
with  severe  diabetes  of  twenty  months'  duration,  weight  42  kg.  He 
had  been  made  sugar-free  by  prolonged  fasting  and  had  been  kept  on 
a  diet  low  in  carbohydrate  and  protein,  as  well  as  fat.  During  the 
twenty-four  hours  of  the  test,  the  urine  contained  but  7  gm.  of  sugar. 
Notwithstanding  this  fact,  the  respiratory  quotient  showed  no  increase, 
but  a  fall  of  2  points.  The  actual  figures  are  not  published  now,  but 
the  comparative  values  may  be  considered  trustworthy.  The  evidence 
in  these  three  cases,  therefore,  points  to  no  utilization  of  the  levulose 
in  two  of  the  cases.  In  one  of  these  most  of  the  levulose  was  probably 
excreted,  but  in  the  other  only  a  negligible  quantity.    In  the  third  case 


TABLE    21. — Effect    of    Potato    on    Respiratory    Quotient    in    Severe 

Diabetes 


Case 
Num- 
ber 

Dura- 
tion 

Montlis 

Montti 

Ob- 
served 

Carbohydrate  Intake 

Sugar  in 

Urine 

24  Hours, 

Gm. 

E.Q. 

Preceding 
Day,  Gm. 

Test  Day, 
Gm. 

Before 

After 

765 

7 

3 

15 

63* 

22 

85 

29 

0.74 

0.73 

806 

(■> 

10 

60+ 
6 

66 

1 
3 

0.68 

•i 

0.71 

*  48  gm.  carb.  as  potato     1 

10  gm.  carb.  as  oatmeal    [  63  gm.       Later  in  day,  22  gm.  carb.  as  potato  and  vegetables 
5  gm.  carb.  as  cream       J    - 

Also  1  egg  and  30  gm.  butter. 
t  60  gm.  carb.  as  potato.  Later  in  day,  1  egg,  butter,  6  gm.  carb.  as  vegetables. 

there  was  an  increase  of  three  points  in  the  respiratory  quotient,  indi- 
cating a  slight  utilization  of  the  levulose  and  there  was  no  excretion 
of  levulose  of  account. 

It  was  possible  to  determine  the  effect  of  the  administration  of 
potato  in  two  cases.  In  the  first  case  the  experiment  was  complicated 
in  that  the  patient  was  given  a  small  quantity  of  oatmeal  at  the  start, 
which,  however,  was  stopped  on  account  of  her  dislike  to  it,  and  potato 
was  substituted.  In  this  case.  No.  765,  no  change  in  the  respiratory 
quotient  took  place,  but  in  the  second.  Case  806,  a  slight  increase  was 
noted,  and  apparently  rather  more  than  would  be  accounted  for  by 
the  limits  of  error. 

Eleven  experiments  have  been  carried  out  on  cases  of  severe  dia- 
betes with  oatmeal.  These  were  arranged  in  some  cases  to  determine 
the  immediate  effect  of  the  administration  of  oatmeal,  and  in  other 
cases   to   determine   the    effect   of    the   prolonged   administration   of 


35 


TABLE  22. — Effect  of  Potato  on  thk   Respiratory   Quotient  of  a   Severe 

Case   of   Diabetes 

Case  806.     Male.  Weight  62  kilos. 


Date 

12/22/14 


Condition 


002  per    Oi  per 

Min.,        Min., 

c.c.  c.c. 


R.  Q. 


Cals.  Blood 

per  Kilo  Sugar 

per  24  Hrs.       Per  Cent. 


25  I 
54 
22 
45 

55 
59 
22 
55 
00 
26 
54 
45 


Fasting. 


Potato   =   60    gm. 
carb. 


166 

150 
155 


181 
168 
172 
170 
157 
166 


223 
224 
228 


257 
252 
250 
233 
227 
231 


0.70] 

O.67I0.6S 

0.681 


24 1 
24  24 


27J 
261 
25  [25 
25J 


0.18 


TABLE   23. — Effect   of    Oatmeal   on    the    Respiratory    Quotient   of   a 

Severe   Diabetic 

Case  nz.    Female.    Weight  40  kilos. 


Date 

Condition 

CO2  per 
Min., 
c.c. 

O2  per 
Min., 
c.c. 

E.  Q. 

Cals. 

per  Kilo 

per  24  Hrs. 

Blood 

Sugar 

Per  Cent. 

10/10/14 
8:00 

11:00 

Fasting 

Oatmeal  =  42  gm. 
carb. 

146 
178 

212    , 
9.49 

0.69 
^.72 

36 
43 

10/13/14 
8.00 

11:00 

Fasting 

138            189 

0.73 

S3 

0.32 
0.27 

0.27 

0.30 
0.34 

10/19/14 
9:00 

12:00 

Fasting 

Oatmeal  =:  80  gm. 
carb. 

135 
167 

195 
•'37 

0.70 
0.70 

34 

40 

10/20/14 

After  breakfast 

Diet  contained  15  gm.  carb.  October  9  and  October  18. 


TABLE    24. — Effect    of    Oatmeal   on   the    Respiratory    Quotient    of 

Severe   Diabetics 


Duration 

Date 

Carbohydrates 
Ignited 

Respiratory 
Quotient 

Sugar 

in 

Urine, 

Gm. 

Carb. 
Intake, 

Carb. 
Bal- 
ance, 
Gm. 

« 

Onset 

to 
Coma, 

Months 

Month 
of 

Test 

No. 

Day 
Preced- 
ing, Gm. 

Before 
Test 
Gm. 

Fast- 
ing 

After 
Oat- 
meal 

194 

•34 

31 

9/22 

15 

0.74 

42 

15 

—27 

9/23 ' 

15 

100-)- 

0.71 

0.71 

50 

165 

-ms 

9/24 

165 

... 

0.72* 

.... 

19 

15 

—4 

246 

15 

11 

8/  9 

50 

40 

0.71 

0.67 

124 

? 

? 

13 

10/29 

65 

60 

0.68 

0.70 

100 

125 

-f25 

10/30 
10/25-31 

125 
71 

... 

0.71* 
0.69 

.... 

93 
102 

65 

72 

—28 
—30 

281 

19 

17 

12/  1 

15 

0.75 

69 

135 

+66 

12/2 

135 

29 

.... 

0.76* 

58 

45 

—13 

12/  3 

45 

0 

0.76 

38 

I    30 

—8 

332 

28 

13 
24 

5/19 
5/26 
4/2 

100 
96 
? 

25± 
52 

0.73 
0.74  ' 

0.73 
0.74 

15 
in  3  brs. 

3 
in  3  hrs. 

97 

26 

6/  2 

? 

48 

0  71 

0.69 

36 

336 

132 

127 

5/18 

20 

0.73 

.... 

26 

45 

-H9 

5/21 

45 

25 

0.75 

SI 

45 

+14 

441 

11 

9 

9/29 

15 

75 

0.70 

0.71 

65 

165 

+100 

10 

10/  9 

15 

73 

0.69 

?■ 

79    ' 

561 

33 

23 

2/  7 

60 

... 

0.75. 

31.1 

60 

+30 

2/  8 

60 

116 

0.71 

0.74 

128.4 

185 

+57 

2/  9 

185 

200 

0.72* 

0.72* 

209.3 

205 

—4 

2/10 

200 

... 

0.76t 

.... 

101.86 

60 

-42 

591 

50 

44 

4/10 

V 

... 

0.74 

63 

30 

—33 

4/11 

30 

0.73 

37 

15 

—22 

4/12 

15 

80 

0.70 

0.70 

85 

165 

+80 

4/13 

165 

80 

0.73* 

0.69* 

77 

165 

+88 

4/15 

40 

0.69 

29 

■I 

773 

20 

18 

10/  8 

115 

70 

0.70 

175.6 

165 

—10 

10/10 

15 

47 

0.69 

0.72 

95.4 

130 

+35 

10/13 

50 

... 

0.73 

83.97 

50 

—34 

10/19 

15 

80 

0.70 

0.70 

96.50 

115 

+18 

746     ■ 

22t 

18 

10/  7 

65 

28 

.... 

0.73 

93.11 

65 

—28 

10/  9 

15 

50 

0.73 

0.71 

86.69 

163 

+76 

10/10 

165 

0.72* 

.... 

34.88 

25 

—10 

10/15 

165 

80 

0.74t 

96.28 

165 

+69 

786 

171 

14 

11/12 

15 

.     60 

0.69 

0.73 

0 

62 

+62 

*  R.  Q.  taken  following  an  oatmeal  day. 
t  R.  Q.  taken  subsequent  to  two  oatmeal 
t  Prior  to  March,  1915. 


days. 


37 

oatmeal.  It  will  be  seen  from  a  study  of  the  tables  that  as  a  rule  the 
respiratory  quotient  remained  stationary  or  fell ;  in  one  case  it  rose  4 
points,  and  in  two  other  cases  it  rose  one  point.  It  will  be  noted 
further  that  the  respiratory  quotient,  when  taken  fasting  on  the  morn- 
ing following  an' oatmeal  day,  amounted  in  three  cases  to  0.73,  0.72  and 
0.73  respectively,  and  that  on  the  morning  following  a  second  oatmeal 
day  it  was  0.69  and  0.76.  The  respiratory  quotient  was  also  deter- 
mined in  three  experiments  after  the  administration  of  carbohydrate 
and  on  the  second  day  it  was  0.72.  If  one  looks  at  the  table  as  a 
whole,  it  will  be  seen  that  little  change  in  the  respiratory  quotient  took 
place:  in  fact,  none  of  any  account  except  on  the  morning  following 
the  second  oatmeal  day. 

The  sum  total  of  the  results  following  the  feeding  of  levulose, 
potato  and  oatmeal  to  severe  diabetics  affords  little  evidence,  from 
the  respiratory  quotient,  that  the  carbohydrate  was  burned,  save  in  the 
case  of  one  of  the  experiments  with  levulose,  one  with  potato,  and  one 
with  oatmeal.  There  results  correspond  closely  with  what  has  been 
recorded  in  the  literature.  Personally,  I  believe  that  before  a  final 
decision  on  this  point  can  be  reached  from  this  particular  line  of  study, 
further  experiments  must  be  performed. 

Unfortunately  in  the  experiments  recorded  no  stated  agreement 
was  noted  between  changes  in  respiratory  quotient  and  variations  in 
the  quantity  of  blood  sugar.  From  Table  6  it  is  evident  that  there  is 
a  general  tendency  for  the  respiratory  quotient  to  rise  with  an  increase 
in  blood  sugar,  but  this  may  be  accidental.  Studies  now  in  progress 
will  soon  throw  light  on  this  phase  of  the  question. 

■V.    ACIDOSIS    AS    A    MEASURE    OF    THE    UTILIZATION    OF    CARBOHYDRATES 

It  has  been  generally  accepted  that  acidosis  will  appear  when  carbo- 
hydrate food  is  either  withdrawn  from  the  diet  or  excreted  in  the 
urine.  It  has  been  unquestionably  the  universal  clinical  experience 
that  the  patient  who  excretes  quantities  of  sugar  in  the  urine  equal  to 
or  in  excess  of  that  in  the  diet  exhibits  acidosis,  and  that  patients  do 
not  show  acidosis  who  are  able  to  utilize  approximately  70  gm.  of 
carbohydrate,  or  large  quantities  of  protein  from  which  carbohydrate 
may  be  formed.  This  statement  cannot  be  so  unqualifiedly  made, 
because  I  have  under  observation  a  woman  who  in  her  sixth  month  of 
pregnancy  showed  over  6  per  cent,  of  sugar,  and  later  under  a  careful 
diet  became  sugar-free,  acquired  a  tolerance  for  approximately  100 
gm.  of  carbohydrate,  and  yet  a  slight  acidosis  persisted.  Neverthe- 
less, the  general  mass  of  evidence  points  to  the  disappearance  of  acid- 
osis when  carbohydrates  are  burned,  and  on  this  general  concept 
arguments  have  been  based  for  and  against  the  utilization  of  carbo- 
hydrate in  severe  diabetes. 


38 

During  von  Noorden's  oatmeal  treatment  a  considerable  quantity 
of  carboh3'drate  ingested  is  usually  retained  or  burned  in  the  body, 
and  the  decrease  of  acidosis  at  the  same  time  is  usually  considered 
evidence  of  the  latter  supposition  being  correct,  but  occasionally  the 
acidosis  persists  although  the  carbohydrates  are  not  excreted.  I  doubt 
if  we  are  in  a  position  to  accurately  explain  the  disappearance  or  non- 
disappearance  of  acidosis  under  these  conditions.  Oatmeal  and  other 
carbohydrates  are  better  retained  in  the  body  following  starvation,  and 
it  is  quite  possible  that  a  mechanical  retention  of  acid  bodies  goes  hand 
in  hand  with  the  retention  of  carbohydrate.  Magnus-Levy  pointed  out 
long  ago  that  these  were  seldom  excreted  in  concentration  of  more 
than  1.5  per  cent.,  and  that  the  fall  in  acidosis  during  an  oatmeal  cure 
may  be  simply  apparent,  because  the  volume  of  urine  excreted  has 
diminished.  The  influence  of  preceding  fasting  is  also  important, 
because  this  undoubtedly  regulates  to  some  extent  the  storage  of  car- 
bohydrate. Despite  these  possibilities,  which  lessen  any  argument  for 
combustion  of  carbohydrate  based  on  the  decrease  of  acidosis  follow- 
ing the  ingestion  of  carbohydrate,  the  slight  amount  of  acidosis  which 
is  usually  found  when  diabetic  patients  are  on  a  full  carbohydrate  diet 
points  strongly  to  the  view  that  some  carbohydrate  is  burned.  The 
increase  in  respiratory  quotient 'on  the  last  days  of  an  oatmeal  cure, 
which  Falta  observed  and  we  also  have  noted,  is  conformatory  to 
this  position. 

Various  writers  have  observed  that  the  acidosis  in  diabetics 
decreases  on  a  vegetable  day  or  fasting  day,  but  it  remained  for  Allen 
to  demonstrate  conclusively  the  remarkable  fact  that  acidosis  vanished 
in  practically  all  severe  cases  of  diabetes  under  these  conditions,  and 
that  in  the  remainder,  if  carbohydrates  to  a  moderate  extent  are 
allowed  temporarily  the  acidosis  wholly  clears  up.  If  a  normal  indi- 
vidual fasts,  it  has  been  the  universal  experience  of  observers  that 
acidosis  appears.  In  other  words,  the  normal  fasting  individual  cor- 
responds with  the  concept  that  when  carbohydrates  are  withdrawn 
from  the  diet  (and  this  implies  carbohydrates  which  might  be  formed 
from  protein)  acidosis  appears.  Thus,  in  the  fasting  man  at  the 
Nutrition  Laboratory,  acidosis  appeared  on  the  second  day  and  con- 
tinued until  the  fast  was  terminated.  How  can  we  reconcile  the  appar- 
ent contradiction  in  the  fact  that  fasting,  which  dissipates  acidosis  in 
diabetes,  produces  it  in  normal  individuals  ?  Must  the  prevalent  concep- 
tion be  given  up  that  carbohydrate  oxidation  and  acidosis  are  unrelated 
and  must  we  acknowledge  that  here  is  an  instance  where  the  absence  of 
the  burning  of  carbohydrates  does  not  lead  to  acidosis?  Such  a  con- 
clusion appeared  unavoidable  until  observations  at  the  Nutrition  Labo- 
ratory on  severe  diabetics  during  prolonged  fasting  began  to  accumu- 


39 

late,  showing  that  whereas  at  the  beginning  of  the  fast  the  respiratory 
quotient  was  the  ordinary  respiratory  quotient  of  severe  diabetes,  0.72, 
with  a  continuance  of  the  fast  this  had  a  tendency  to  rise  several 
points,  occasionally  even  to  the  neighborhood  of  0.80.  Later  experi- 
ments, as  yet  unpublished,  at  the  Russell  Sage  Laboratory  made  under 
the  direction  of  Dr.  DuBois  and  Professor  Lusk  on  one  of  Dr.  Allen's 
patients  suggested  a  similar  condition.  In  other  words,  whereas  the 
normal  individual  showing  acidosis  exhibits  a  respiratory  quotient 
based  on  the  combustion  of  protein  and  fat  alone,  the  severely  affected 
diabetic  during  fasting  shows  a  respiratory  quotient  which  could  be 
accounted  for  only  by  the  combustion  of  notable  quantities  of  material 
other  than  fat  and  protein.  That  this  material  was  not  protein  was 
evident,  because  the  amounts  of  nitrogen  in  the  urine  excreted  during 
these  periods  were  not  abnormal.  This  increase  in  the  respiratory 
quotient  furnishes  the  explanation  of  the  fact  that  the  severely  afTected 
diabetic  in  contradistinction  to  the  normal  individual,  shows  no  acidosis 
during  a  fast. 

Several  explanations  for  this  increase  in  the  respiratory  quotient  of 
fasting  diabetics  are  available.  During  fasting  the  diabetic  may  be 
able  to  draw  on  sources  of  carbohydrate  in  the  body  which  the  norm.al 
individual  cannot.  Furthermore,  the  diabetic  has  in  the  body  undoubt- 
edly more  carbohydrate  stored  than  we  have  hitherto  supposed,  and 
the  supposition  must  be  entertained  that  the  diabetic  really  may  actu- 
ally have  more  carbohydrate  in  some  form  in  the  body  than  exists  in 
the  normal  individual.  A  third  supposition  for  the  increase  in  the 
respiratory  quotient  is  that  considerable  quantities  of  acid  bodies  have 
accumulated  and  that  with  the  improvement  of  the  condition  of  the 
patient  during  fasting  these  are  burned.  It  will  be  remembered  that 
beta-oxybutyric  acid,  diacetic  acid  and  acetone  all  have  relatively 
high  respiratory  quotients,  namely,  0.89,  1.00  and  0.75  respectively,  and 
therefore  the  oxidation  of  a  small  quantity  of  these  substances  would 
markedly  raise  the  respiratory  quotient.  Which  of  these  suppositions 
is  correct  will  be  eventually  known  because  of  the  improved  methods 
of  estimating  carbohydrate  and  acid  bodies  in  the  blood,  fluids  and 
tissues  of  the  body,^**  and  also  by  the  help  which  is  afforded  from  the 
estimation  of  the  carbon  dioxid  tension  of  the  blood. 

I  should  like  to  point  out  this  further  possibility :  During  prolonged 
fasting,  acidosis  tends  to  disappear,  in  part  because  the  sources  of  the 
acid  bodies,  save  for  body  fat  and  protein,  have  been  eliminated.  So 
soon  as  acidosis  begins  to  decrease,  there  is,  as  we  and  others  have 
found,  a  lessening  of  the  total  metabolism,  and  with  this  lessening  of 
total  metabolism  an  improvement  in  the  combustion  of  carbohydrate 


39.  Marriott :  Jour.  Am.  Med.  Assn.,  1914,  Ixiii,  397. 


40 

takes  place.  This  in  turn  favors  the  combustion  of  acid  bodies.  It 
might  well  be  that  the  first  step  to  take  in  the  treatment  of  a  case  of 
diabetes  is  to  abolish  acidosis  completely. 

All  may  be  ready  to  concede  that  all  diabetic  patients  under  fasting 
conditions  are  burning  carbohydrates,  but  some  may  say  t'hat  the 
character  of  the  disease  has  changed,  and  instead  of  being  a  severe 
type  of  diabetes  the  case  has  become  one  of  moderate  severity.  Such 
a  criticism  is  hard  to  answer.  It  presupposes,  however,  that  an  indi- 
vidual can  readily  change  in  the  space  of  a  few  hours  from  a  state  in 
which  death  is  imminent  to  one  of  safety,  and  that  so  fundamental  a 
function  as  the  loss  of  power  to  utilize  carbohydrates  can  be  quickly 
regained.  This  would  be  a  remarkable  phenomenon.  Against  this 
explanation  also  is  the  fact  that  many  who  have  employed  fasting 
treatment  with  severe  cases  of  diabetes  have  regretfully  acknowledged 
that  either  very  slight  or  no  increase  of  tolerance  for  carbohydrates 
has  been  produced  in  these  patients.  This  would  make  it  still  more 
unlikely  that  the  diabetic  patient  by  fasting  altered  his  nature.  It 
would  rather  point  to  the  view  that  the  diabetic  condition  remained 
unchanged,  but  that  during  fasting  the  diabetic  was  able  to  secure  and 
burn  material  which  under  other  conditions  he  could  not  reach,  and 
which  the  normal  individual  could  not  secure. 

In  conclusion  it  is  gratifying  to  be  able  to  record  that  the  recent 
experimental  evidence  confirms  the  old  clinical  view  that  the  severe 
diabetic  still  retains  power  to  utilize  a  portion  of  the  carbohydrate  of 
his  diet,  small  though  it  may  be  and  that  herein  lies  renewed  hope  for 
the  success  of  treatment. 
81  Bay  State  Road. 


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